COVID-19 and Diabetes: A Collision and Collusion of Two ...COVID-19 and Diabetes: A Collision and Collusion of Two Diseases Eva L. Feldman,1,2 Masha G. Savelieff,1,2 Salim S. Hayek,3

COVID-19 and Diabetes: A Collision and Collusion ofTwo DiseasesEva L. Feldman,1,2 Masha G. Savelieff,1,2 Salim S. Hayek,3 Subramaniam Pennathur,4 Matthias Kretzler,4

and Rodica Pop-Busui5

Diabetes 2020;69:2549–2565 | https://doi.org/10.2337/dbi20-0032

The coronavirus disease 2019 (COVID-19) pandemic hasinfected >22.7 million and led to the deaths of 795,000people worldwide. Patients with diabetes are highly sus-ceptible to COVID-19–induced adverse outcomes andcomplications. The COVID-19 pandemic is superimpos-ing on the preexisting diabetes pandemic to create largeand significantly vulnerable populations of patients withCOVID-19 and diabetes. This article provides an over-view of the clinical evidence on the poorer clinical out-comes of COVID-19 infection in patients with diabetesversus patients without diabetes, including in specific pa-tient populations, such as children, pregnant women, andracial and ethnicminorities. It also draws parallels betweenCOVID-19 and diabetes pathology and suggests that pre-existing complications or pathologies in patients with di-abetesmight aggravate infection course. Finally, this articleoutlines the prospects for long-term sequelae after COVID-19 for vulnerable populations of patients with diabetes.

The coronavirus disease 2019 (COVID-19) pandemic hasinfected.22.7 million and killed.795,000 people world-wide, as of 21 August 2020 (1). COVID-19 infection iscaused by severe acute respiratory syndrome coronavirus2 (SARS-CoV-2), a single-stranded RNA b-coronavirus (2).Patients with diabetes are highly susceptible to adverseoutcomes and complications of COVID-19 infection (3).The COVID-19 pandemic is superimposing on the preex-isting diabetes pandemic to create large and significantlyvulnerable populations of patients with COVID-19 anddiabetes. Other comorbid conditions frequent in patientswith type 2 diabetes, e.g., cardiovascular disease (CVD) and

obesity, also predispose COVID-19 patients to adverseclinical outcomes (4,5).

SARS-CoV-2 pathophysiology remains incompletely un-derstood, but evidence suggests it triggers hyperinflam-mation in certain patients (6) and that tissue tropism isexhibited (7), pathologies shared with chronic inflamma-tion and multitissue damage in diabetes (8). COVID-19infection disrupts glucose regulation, rendering glycemiccontrol difficult and necessitating particularly careful man-agement in patients with diabetes (9). Moreover, earlyindicators and comparison with the previous severe acuterespiratory syndrome coronavirus (SARS-CoV) outbreak(10) suggest that survivors may face sequelae, which willrequire long-term care. Currently, the U.S. and some othercountries are experiencing surges in COVID-19 cases (1).This article will review the current state of knowledge ofCOVID-19 and diabetes to address nine critical questions,some of which remain unanswered (Fig. 1).

Review MethodologyWe initially performed our literature search on PubMedwithout any filters on publication date and completed itby 10 July 2020. The search keywords varied by section.For the diabetes and comorbidities section, we searched“COVID-19” or “SARS-CoV-2” with “clinical characteris-tics,” “clinical cohort,” “clinical,” or “cohort,” and priori-tized clinical, high-quality medical studies. We did notgenerally include meta-analyses and excluded preprints,since we had sufficient peer-reviewed material. To the bestof our ability, we selected studies that appeared to reportdifferent patient cohorts, considering some cohorts may

1Department of Neurology, University of Michigan, Ann Arbor, MI2NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI3Division of Cardiology, Department of Internal Medicine, University of Michigan,Ann Arbor, MI4Division of Nephrology, Department of Internal Medicine, University of Michigan,Ann Arbor, MI5Division of Metabolism, Endocrinology and Diabetes, Department of InternalMedicine, University of Michigan, Ann Arbor, MI

Corresponding author: Eva L. Feldman, [email protected]

Received 15 July 2020 and accepted 10 September 2020

This article is part of a special article collection available at https://diabetes.diabetesjournals.org/collection/diabetes-and-COVID19-articles.

E.L.F. and M.G.S. were equal contributing authors.

© 2020 by the American Diabetes Association. Readers may use this article aslong as the work is properly cited, the use is educational and not for profit, and thework is not altered. More information is available at https://www.diabetesjournals.org/content/license.

Diabetes Volume 69, December 2020 2549

PERSPECTIVES

INDIA

BETES

https://doi.org/10.2337/dbi20-0032http://crossmark.crossref.org/dialog/?doi=10.2337/dbi20-0032&domain=pdf&date_stamp=2020-11-07mailto:[email protected]://diabetes.diabetesjournals.org/collection/diabetes-and-COVID19-articleshttps://diabetes.diabetesjournals.org/collection/diabetes-and-COVID19-articleshttps://www.diabetesjournals.org/content/licensehttps://www.diabetesjournals.org/content/license

have been duplicated without reporting it (11). However,we may have included studies from the same cohort if thestudy focus was different. We focused on China, U.S., andEurope as the early epicenters. We also repeated the searchwith the keyword “diabetes,” “acute kidney injury,” or “acutecardiac injury.”We read all abstracts to select relevant manu-scripts, which we searched for the term “diabetes” and allrelevant information. During the revision process, weupdated the review with relevant literature (same criteria)published up until 18 August. For the pediatric section, wesearched “COVID-19” or “SARS-CoV-2” and “diabetes” with“pediatric,” “childhood,” “children,” “youth,” or “adolescent.”For the pregnancy section, we searched “COVID-19” or“SARS-CoV-2” and “diabetes” with “pregnant,” “pregnancy,”or “gestational.” For the race section, we searched “COVID-19” or “SARS-CoV-2” and “race,” “black,” “African American,”“Hispanic,” or “Asian” and prioritized high-quality clinicalstudies. We also performed a subsearch using “diabetes.”

Diabetes and COVID-19

General COVID-19 Patient CohortsAlthough the COVID-19 pandemic evolved quickly, therewere clear early warning signs that comorbidities, includingdiabetes, predisposed patients to adverse outcomes (Table1). The first reports that emerged from Wuhan, China,documented that diabetes raised the risk of dangerousinfection-induced adverse outcomes and complications,leading to acute respiratory distress syndrome (ARDS),intensive care unit (ICU) admission, mechanical ventilationuse, and greater risk of death (12,13). In univariate logisticregression analysis, diabetes had an odds ratio (OR) of 2.85for in-hospital death (13). At the national level, severalChina studies found association of diabetes with severedisease (ICU, mechanical ventilation) (14) and death (14,15).

These findings are replicated in the U.S., where diabetesis one of the three most common comorbid conditionsnationwide, with total comorbidity prevalence as high as78% among ICU COVID-19 admissions (n 5 457 total)(16). In New York City (NYC), patients with diabetes weremore likely to need mechanical ventilation or ICU admis-sion (17,18). In a different NYC cohort, the diabetesunivariate hazard ratio (HR) for in-hospital mortalitywas 1.65, which did not persist in multivariate analysisafter adjustment for age, sex, and seven additional param-eters (5). In Detroit (n5 463), diabetes was more frequentin hospitalized versus discharged and ICU versus non-ICUpatients but was not a risk in multivariate analysis (19).Diabetes was an independent risk for hospital admission(OR 2.24, with full adjustment for patient characteristicsand comorbidities) but not for critical disease or death ina large NYC cohort (n 5 5,279) (20).

In other countries, a German study (n 5 50) found nodifferences in diabetes frequency in ARDS versus non-ARDS patients (21), though these outcomes contrast withthose of another study in China (22). An observationalU.K. study (n5 1,157) found that diabetes had an age- andsex-adjusted HR of 1.42 for critical care and could beintegrated into a 12-point prognostic risk score (criticalcare admission, death) (23), similar to another 10-variablerisk score (24). Collectively, these general cohort studiessuggest that patients with diabetes have a higher likeli-hood of adverse outcomes, although other mitigating riskfactors likely exist, contributing to the varying conclusions.

Cohorts of Patients With COVID-19 and DiabetesSeveral reports have focused specifically on cohorts ofpatients with diabetes. The multicenter French Coronavi-rus SARS-CoV-2 and Diabetes Outcomes (CORONADO)

Figure 1—Outstanding questions on diabetes in the context of COVID-19.

2550 COVID-19 and Diabetes: Collision and Collusion Diabetes Volume 69, December 2020

Tab

le1—

Ove

rview

ofad

ultCOVID

-19clinical

coho

rts

Study

Loca

tion

Partic

ipan

ts(n)

Diabetes

find

ings

Com

orbidities

find

ings

*Selec

tlaboratoryfind

ings

**

Wan

get

al.

(12)

Wuh

an,China

138

Patientswith

diabetes

cons

tituted

22.2%

ofICU

patientsvs.5.9%

ofno

n-ICU

patients,

P5

0.00

9

CVD,hy

pertens

ion,

cerebrova

scular

disea

sepredispos

edto

ICU

Eleva

tedWBC,n

eutrop

hils,A

LT,A

ST,

CK-M

B,

Cr,

D-dim

er,hs

-TnI,LD

H,PCT,

and

lympho

pen

iain

ICU

vs.no

n-ICU

patients

Zho

uet

al.(13

)Wuh

an,China

191

Patientswith

diabetes

cons

tituted

31%

ofno

nsurvivo

rsvs.14

%of

survivors(P

50.00

51);OR

2.85

(95%

CI1.35

–6.05

;P5

0.00

62)forin-hos

pita

ldea

thin

aun

ivariate

mod

el

CVD,24

%no

nsurvivo

rsvs.1%

survivors(P

,0.00

01),OR

21.40(95%

CI4.64

–98

.76;

P,

0.00

01)in

univariate

mod

el;hy

pertens

ion,

48%

nons

urvivo

rsvs.23

%su

rvivors(P

50.00

08),OR

3.05

(95%

CI1.57

–5.92

;P5

0.00

10)in

univariate

mod

el

Eleva

tedWBC,ALT

,CK,Cr,

D-dim

er,ferritin,

hs-TnI,IL-6,LD

H,PT,

andPCTha

dsign

ifica

ntHR

.1fordea

thin

univariate

mod

el;D-dim

erha

dsign

ifica

ntHR

.1for

dea

thin

multiv

ariate

mod

el

Gua

net

al.

(14)

China

1,09

916

.2%

ofpatientswith

seve

revs.5.7%

with

nons

evereCOVID-19infections

had

diabetes

,an

d26

.9%

that

met

vs.6.1%

that

did

notm

eetthe

prim

aryco

mpos

iteen

dpoint

(ICU,mec

hanica

lven

tilationus

e,dea

th)ha

ddiabetes

;no

Pva

lues

5.8%

ofse

vere

vs.1.8%

ofno

nsev

ereCOVID-

19patientsha

dCHD,a

nd9.0%

that

met

vs.

2.0%

that

did

notmee

ttheprim

ary

compos

iteen

dpoint

hadCHD;23

.7%

ofse

vere

vs.13

.4%

ofno

nsev

ereCOVID-19

patientsha

dhy

pertens

ion,

and35

.8%

that

met

vs.13

.7%

that

did

notmee

ttheprim

ary

compos

iteen

dpoint

hadhy

pertens

ion;

noPva

lues

Eleva

tedWBC,ALT

,AST,

CRP,D-dim

er,LD

H,

PCT,

andlympho

pen

iain

seve

revs.

nons

evereinfectionan

din

patientsthat

met

vs.did

notmee

ttheprim

aryco

mpos

iteen

dpoint,no

Pva

lues

Wuan

dMcG

ooga

n(15)

China

72,314

total,

44,672

confi

rmed

(factored

into

CFR

)

CFR

7.3%

inpatientswith

diabetes

vs.2.3%

fortheen

tireco

hort

CFR

10.5%

forCVD,6.0%

forhy

pertens

ion

Not

exam

ined

Richa

rdso

net

al.(17)

NYC

area

5,70

0Diabetes

oneof

threemos

tco

mmon

morbidities

.Patientswith

diabetes

more

likelyto

need

mec

hanica

lven

tilationor

ICU

Hyp

ertens

ionan

dob

esity

twoof

threemos

tco

mmon

morbidities

.Hyp

ertens

ivepatients

less

likelyto

need

mec

hanica

lven

tilationor

ICU;88

%of

COVID-19patientsha

dtw

oor

moreco

morbidities

compared

with

one

(6.3%

)or

none

(6.1%

).

Eleva

tedALT

,AST,

BNP,C

RP, D

-dim

er,ferritin,

LDH,PCT,

andlympho

pen

iain

hosp

italized

COVID-19patients

Goy

alet

al.

(18)

NYC

393

Diabetes

was

morefreq

uent

inpatients

requirin

gmec

hanica

lven

tilation(27.7%

)vs.no

t(24.0%

)(P

valueno

tstated

)

Hyp

ertens

ion,

CAD,an

dob

esity

weremore

freq

uent

inpatientsrequirin

gmec

hanica

lve

ntilatio

n(P

values

notstated

)

Majority

ofpatientsha

dlympho

pen

ia(90.0%

),thromboc

ytop

enia

(27%

);man

yha

delev

ated

liver

func

tionva

lues

andinflam

matory

marke

rs(CRP,D-dim

er,ferritin,

PCT),which

werefurthe

rincrea

sedin

patientsrequirin

gmec

hanica

lven

tilation

Cum

mings

etal.(5)

NYC

1,15

0Diabetes

oneof

threemos

tco

mmon

morbidities

.Univa

riate

HR

1.65

(95%

CI

1.11

–2.44

),no

tsign

ifica

ntin

multiv

ariate

HR

1.31

(95%

CI0.81

–2.10

)forin-hos

pita

lmortality

Hyp

ertens

ionan

dob

esity

twoof

threemos

tco

mmon

morbidities

.Hyp

ertens

ion

univariate

HR2.24

(95%

CI1

.40–

3.59

);CCD

univariate

HR

2.21

(95%

CI1.44

–3.39

),multiv

ariate

HR

1.76

(95%

CI1.08

–2.86

);BMI$

40kg

/m2no

tsign

ifica

ntun

ivariate

HR

0.76

(95%

CI0.40

–1.47

)forin-hos

pita

lmortality;

CKD

was

notaris

kforin-hos

pita

ldea

th

Asidefrom

othe

ralte

redmarke

rs,IL-6un

ivariate

HR1.12

(95%

CI1

.04–

1.21

)and

multiv

ariate

HR

1.11

(95%

CI1.02

–1.20

)an

dD-dim

erun

ivariate

HR

1.18

(95%

CI1.10

–1.27

)an

dmultiv

ariate

HR

1.10

(95%

CI1.01

–1.19

)for

in-hos

pita

lmortality

Con

tinue

don

p.25

52

diabetes.diabetesjournals.org Feldman and Associates 2551

Tab

le1—

Continue

dStudy

Loca

tion

Partic

ipan

ts(n)

Diabetes

find

ings

Com

orbidities

find

ings

*Selec

tlaboratoryfind

ings

**

Suley

man

etal.(19)

Detroit,

MI

463

Diabetes

was

morefreq

uent

inho

spita

lized

(43.4%

)vs.

disch

arge

d(20.4%

)patients(P

,0.00

1).Itwas

also

morefreq

uent

inICU

(51.8%

)vs.no

n-ICU

(38.8%

)patients(P

50.02

)but

was

notaris

kin

multiv

ariate

analysis

forICU

ormec

hanica

lven

tilation.

African

American

race

was

notm

orefreq

uent

inad

mitted

orICUvs.d

isch

arge

dpatientsor

aris

kformec

hanica

lven

tilationor

dea

th

Hyp

ertens

ion,

CVD,ob

esity

,an

dCKD

were

morefreq

uent

inho

spita

lized

vs.disch

arge

dpatients.

Hyp

ertens

ionan

dCKD

werealso

morefreq

uent

inICU

vs.no

n-ICU

patients.

CKD

andse

vere

obes

itywereris

ksin

multiv

ariate

analysis

forICU

ormec

hanica

lve

ntilatio

n

Eleva

tedAST,

Cr,an

dhs

-TnI;lower

WBC;an

dlympho

pen

iain

hosp

italized

vs.disch

arge

dpatientsbyun

ivariate

analysis.Eleva

ted

WBC,A

ST,

Cr,

D-dim

er,ferritin,h

s-Tn

I,LD

H,

PCT,

andlympho

pen

iain

ICU

vs.no

n-ICU

patientsbyun

ivariate

analysis

Petrilliet

al.

(20)

NYC

5,27

9Diabetes

hadmultiv

ariate

OR

2.24

(95%

CI

1.84

–2.73

;P,

0.00

1)forh

ospita

ladmission

,with

adjustmen

tforpatient

charac

teris

tics,

comorbidities

Allmultiv

ariate:he

artfailure

OR

4.43

(95%

CI

2.59

–8.04

;P,

0.00

1),hy

pertens

ionOR

1.78

(95%

CI1.49

–2.12

;P,

0.00

1),CKD

OR

2.6(95%

CI1.89

–3.61

;P,

0.00

1),

hyperlip

idem

iaOR

0.62

(95%

CI0.52

–0.74

;P,

0.00

1),B

MI25.0–

29.9

kg/m

2(ove

rweigh

t)OR

1.3(95%

CI1.07

–1.57

;P5

0.00

7),BMI

30–39

.9kg

/m2(obes

eclas

sIan

dII)

OR

1.8

(95%

CI1.47–

2.2;

P,

0.00

1),B

MI$

40kg

/m2

(obes

eclas

sIII)O

R2.45

(95%

CI1

.78–

3.36

;P,

0.00

1);allfor

hosp

itala

dmission

,ad

justed

forsa

meva

riablesas

diabetes

Eleva

tedCr,CRP,D-dim

er,PCT,

trop

onin,an

dlympho

pen

iain

critica

lCOVID-19

Drehe

ret

al.

(21)

Aac

hen,

German

y50

Diabetes

did

notraisetheris

kforARDS;no

Pva

lues

Obes

ity,but

nothy

pertens

ion,

raised

theris

kforARDS;no

Pva

lues

Eleva

tedWBC,CK,CRP,D-dim

er,IL-6,LD

H,

andPCT;

noPva

lues

Wuet

al.(22)

Wuh

an,China

201

Diabetes

was

morefreq

uent

inARDS(19.0%

)than

non-ARDS(5.1%)patients(P

50.00

2);

riskforARDS(HR

2.34

[95%

CI1.35

–4.05

];P5

0.00

2)but

notdea

th(HR

1.58

[95%

CI

0.80

–3.13

];P5

0.19

)

Hyp

ertens

ionwas

morefreq

uent

inARDS

(27.4%

)than

non-ARDS(13.7%

)patients

(P5

0.02

),ris

kforARDS(HR

1.82

[95%

CI

1.13

–2.95

];P5

0.01

)but

notdea

th(HR1.70

[95%

CI0.92

–3.14

];P5

0.09

)

Eleva

tedne

utrophils,AST,

CRP,D-dim

er,

ferritin,

LDH,and

PTha

dsign

ifica

ntHR.1for

ARDS;ne

utrophils,D-dim

er,IL-6,an

dLD

Hha

dsign

ifica

ntHR

.1fordea

th

Galloway

etal.

(23)

U.K.

1,15

7Diabetes

hadHR

(adjustmen

tforse

x,ag

e)of

1.42

forcritica

lcare(95%

CI1.04

–1.95

;P5

0.02

9)

Hyp

ertens

ionha

dHR(adjusted

forse

x,ag

e)of

1.53

forcritica

lcareor

dea

th(95%

CI1.24

–

1.90

;P5

0.00

0)

Neu

trop

hils,C

r,an

dCRPha

dsign

ifica

ntHR.1

forcritica

lcareor

dea

th

Lian

get

al.

(24)

China

1,59

0,disco

very

coho

rt;71

0,va

lidation

coho

rt;ris

ksc

oreforcritica

lillne

ss

6.8%

nonc

ritical

vs.23

.7%

critica

ldisea

seam

ongpatientswith

diabetes

3.2%

nonc

ritical

vs.9.9%

critica

ldisea

seam

ongCVD

patients;

14.8%

nonc

ritical

vs.

40.5%

critica

ldisea

seam

onghy

pertens

ion

patients.

Num

ber

ofco

morbidities

hadOR

1.60

(95%

CI1.27

–2.00

;P,

0.00

1)in

multiv

ariate

analysis

Asidefrom

othe

ralte

redmarke

rs,n

eutrop

hil-to-

lympho

cyte

ratio

(OR

1.06

[95%

CI1.02

–

1.10

];P5

0.00

3)an

dLD

H(OR1.00

2[95%

CI

1.00

1–1.00

4];P,

0.00

1)integrated

into

a10

-point

risksc

oreforcritica

lillnes

s

Cariouet

al.

(25)

Fran

ce1,31

7,of

who

m1,16

6with

T2D

Diabetes

type,

HbA1c,gluc

ose-lowering

therap

yus

edid

notaffect

prim

aryou

tcom

e(m

echa

nica

lven

tilationan

d/ordea

thwith

in7day

sof

admission

)in

univariate

analysis

Micro-(OR

2.14

[95%

CI1.16

–3.94

];P5

0.01

53)a

ndmac

rova

scular

(OR2.54

[95%

CI

1.44

–4.50

];P5

0.00

13)co

mplications

indep

enden

tlyas

sociated

with

7-day

mortality;

BMImultiv

ariate

OR

1.28

(95%

CI

1.10

–1.47

),P,

0.00

10forco

mpos

ite

AST(OR2.23

[95%

CI1

.70–

2.93

];P,

0.00

01)

andCRP(O

R1.93

[95%

CI1.43

–2.59

];P,

0.00

01)indep

enden

tlyas

sociated

with

prim

aryou

tcom

e;high

erlympho

cyteswere

protective(O

R0.67

[95%

CI0.50

–0.88

];P5

0.00

50)

Con

tinue

don

p.25

53


Tab

le1—

Continue

dStudy

Loca

tion

Partic

ipan

ts(n)

Diabetes

find

ings

Com

orbidities

find

ings

*Selec

tlaboratoryfind

ings

**

Barronet

al.

(26)

U.K.

23,698

COVID-

19dea

ths,

364T1

DCOVID-19

dea

ths,

7,43

4T2

DCOVID-19

dea

ths

T1DOR2.86

(95%

CI2

.58–

3.18

;P,

0.00

1)an

dT2

DOR1.80

(95%

CI1

.75–

1.86

;P,

0.00

1)fordea

th,with

adjustmen

tforag

e,se

x,dep

rivation,

ethn

icity

,CVD,ce

rebrova

scular

disea

se

CVD

andce

rebrova

scular

disea

semore

freq

uent

inT1

Dan

dT2

Dvs.no

ndiabetes

inCOVID-19dea

ths

Not

exam

ined

Zha

nget

al.

(27)

Wuh

an,China

258,

ofwho

m63

with

diabetes

Diabetes

hadmultiv

ariate

HR

3.64

(95%

CI

1.09

–12

.21;

P5

0.03

6);elev

ated

FBG

(.7.54

mmol)h

admultiv

ariate

HR1.19

(95%

CI1.08

–1.31

;P,

0.00

1);bothfordea

thad

justed

forag

e,CVD,CKD,inflam

matory

marke

rs

CVD

morefreq

uent

inpatientswith

diabetes

(23.8%

)vs.patientswith

outdiabetes

(12.3%

),P5

0.02

7;CKD

morefreq

uent

inpatientswith

diabetes

(8.8%)vs

.patients

with

outpatients(2.1%),P5

0.02

7

Eleva

tedWBC,ne

utrophils,CK-M

B,D-dim

er,

TTin

patientswith

diabetes

vs.patients

with

outdiabetes

Guo

etal.(28)

Wuh

an,China

174,

overall

analysis;50

,su

bgrou

pan

alysis

Patientswith

diabetes

with

outan

yothe

rco

morbidities

(16.5%

)diedmoreoftenthan

patientswith

outdiabetes

with

out

comorbidities

(0%)(P

50.03

);ho

wev

er,the

latter

patientswereyo

unge

r

CVD

was

morepreva

lent

inpatientswith

diabetes

,P5

0.01

3Eleva

tedne

utrophils,D-dim

er,an

dESR,an

dlympho

pen

iain

patientswith

diabetes

vs.

patientswith

outdiabetes

;ne

utrophils,ALT

,CRP,D-dim

er,ESR,ferritin,

IL-6,LD

H,an

dlympho

pen

iain

patientswith

diabetes

vs.

patientswith

outdiabetes

with

out

comorbidities

;ho

wev

er,thelatter

patients

wereyo

unge

r

Zhu

etal.(3)

Hub

eiProvinc

e,China

7,33

7,of

who

m95

2with

T2D

T2D

patientsha

dhigh

ermortality:

7.8%

vs.

2.7%

overall,ad

justed

HR1.49

(95%

CI1.13–

1.96

;P5

0.00

5);well-co

ntrolledblood

gluc

oseco

nferslower

all-ca

usemortality,

adjusted

HR

0.14

(95%

CI0.03

–0.60

;P5

0.00

8)

Blood

gluc

oseco

rrelated

with

comorbid

CHD,

hypertens

ion

T2D

patientsha

delev

ated

WBC,ne

utrophils,

Cr,CRP,D-dim

er,IL-6,LD

H,PCT,

and

lympho

pen

iavs.patientswith

outdiabetes

;T2

Dpatientswith

well-co

ntrolledvs

.poo

rlyco

ntrolledblood

gluc

oseha

dsign

ifica

ntly

fewer

inciden

cesof

elev

ated

WBC,

neutrophils,ALT

,AST,

Cr,CRP,D-dim

er,

PCT,

andlympho

pen

ia;no

Pva

lues

Iaco

bellis

etal.(29)

Miami,FL

85Admission

hyperglyc

emia

bes

tpredictedpoo

rch

estradiologica

loutco

mes

BMIco

rrelated

with

poo

rch

estradiologica

lou

tcom

esNot

exam

ined

Liet

al.(30)

Wuh

an,China

132,

ofwho

m13

0with

T2D

Patientswith

diabetes

stratifi

edbyad

mission

gluc

ose:

grou

p1(#

11mmol/L)vs

.grou

p2(.

11mmol/L);grou

p2ha

dlong

erdiabetes

duration,

morelikelyto

suffer

ACI,ICU

admission

,dea

th

Nodifferen

cein

comorbidities

ingrou

p1vs.

grou

p2

Eleva

tedWBC,CRP,D-dim

er,ESR,IL-6,an

dlympho

pen

iain

grou

p2vs.grou

p1;

WBC

(.10

9/L),Cr(,

57/0

mmol/L),

D-dim

er($

1.5

mg/L),hs

-TnI

(.26

.2pg/mL),LD

H(.

245

units

/L),PCTun

ivariate

OR.1forin-ho

spita

lco

mplications

Cha

oet

al.

(31)

Taiwan

452

Highgluc

oseva

riability

with

inthefirstday

ofICU

admission

correlated

with

30-day

mortality,

partic

ularly

inpatientswith

out

diabetes

.Highgluc

oseva

riability

was

more

freq

uent

inpatientswith

diabetes

Exc

eptfordiabetes

,no

differen

cein

othe

rco

morbidities

(e.g.,CKD,CHD,

cerebrova

scular

disea

se)inpatientswith

high

vs.low

gluc

oseva

riability;APACHEIIsc

ore

indep

enden

tlyco

rrelated

with

high

er30

-day

mortality

Nodifferen

cesin

Cr,CRP,a

ndPCTin

patients

with

high

vs.low

gluc

oseva

riability

Con

tinue

don

p.25

54


Tab

le1—

Continue

dStudy

Loca

tion

Partic

ipan

ts(n)

Diabetes

find

ings

Com

orbidities

find

ings

*Selec

tlaboratoryfind

ings

**

Bod

eet

al.

(32)

U.S.

1,12

2Diabetes

and/orun

controlledhy

perglyc

emia

increa

sedho

spita

llen

gthof

stay

and

mortality

Kidne

yfunc

tion,

asas

sessed

byeG

FR,was

lower

inpatientswith

diabetes

and/or

unco

ntrolledhy

perglyc

emia

atad

mission

Eleva

tedCrin

patientswith

diabetes

and/or

unco

ntrolledhy

perglyc

emia

vs.patients

with

outdiabetes

orwith

controlledblood

gluc

osepatients

Williamso

net

al.(4)

U.K.

10,926

COVID-

19dea

thsvs

.17

,278

,392

controls

ubjects

Diabetes

with

HbA1c,7.5%

(58mmol/m

ol),HR

1.31

(95%

CI1.24

–1.37

),an

dwith

HbA1c$7.5%

(58mmol/m

ol),HR1.95

(95%

CI1.83

–2.07

),fordea

th,ad

justed

forag

e,se

x,co

morbidities

,sm

oking,

socioe

cono

mic

status

.Mixed

race

,HR

1.43

(95%

CI1.11

–

1.85

);Sou

thAsian

,HR

1.44

(95%

CI1.32

–

1.58

);an

dBlack

,HR1.48

(95%

CI1

.30–

1.69

);ris

ksfordea

thafterad

justmen

tforthesa

me

varia

bles

BMI30

–34

.9kg

/m2(obes

eclas

sI)

nons

ignifica

ntHR

1.05

(95%

CI1.00

–1.11

),BMI35

–39

.9kg

/m2(obes

eclas

sII)

HR

1.40

(95%

CI1.30

–1.52

),BMI$40

kg/m

2(obes

eclas

sIII)HR

1.92

(95%

CI1.72

–2.13

),hy

pertens

ionHR

0.89

(95%

CI0.85

–0.93

),CHD

HR

1.17

(95%

CI1.12

–1.22

),reduc

edkidne

yfunc

tioneG

FR30

–60

mL/min/1.73m

2

HR1.33

(95%

CI1

.28–

1.40

),eG

FR,30

mL/

min/1.73m

2HR

2.52

(95%

CI2.33

–2.72

),stroke

/dem

entia

HR2.16

(95%

CI2

.06–

2.27

),fordea

th,ad

justed

forthesa

meparam

eters

asdiabetes

Not

exam

ined

Holman

etal.

(33)

U.K.

464T1

DCOVID-19

dea

ths,

10,525

T2D

COVID-19

dea

ths

T1D:HbA1c$10

.0%

(86mmol/m

ol)HR

2.23

,T2

D:HbA1c7.5–

8.9%

(59–

74mmol/m

ol)HR

1.22

(95%

CI1.15

–1.30

),HbA1c9.0–

9.9%

(75–

85mmol/m

ol)HR

1.36

(95%

CI1.24

–

1.50

),HbA1c$10

.0%

(86mmol/m

ol)H

R1.61

(95%

CI1

.47–

1.77

);allP

,0.00

01,a

djusted

forag

e,se

x,dep

rivation,

ethn

icity

,clinical,

CVD,CKD,am

ongothe

rs

T1D:inv

erse

relatio

nof

eGFR

with

HR;U

-sha

pe

relatio

nof

BMIwith

HR,referenc

eto

overweigh

tca

tego

ry(BMI25

.0–29

.9kg

/m2);

CVD

HR.1,

nosign

ifica

nceof

hypertens

ion

andch

oles

terol.T2

Dha

dthesa

meris

ks,p

lus

hypertens

ionHR

,1

Not

exam

ined

Zha

nget

al.

(34)

Wuh

an,China

166

Diabetes

andhy

perglyc

emia

seco

ndaryto

COVID-19increa

setheris

kof

critica

ldisea

se(32.8%

and38

.1%,resp

ectiv

ely,

vs.9.5%

overall,P,

0.05

forboth)

andco

mpos

iteou

tcom

e(IC

U,mec

hanica

lven

tilationus

e,dea

th)

Hyp

ertens

ionwas

freq

uent

inpatientswith

diabetes

andse

cond

aryhy

perglyc

emia

(P5

0.02

9)

Eleva

tedWBC,ne

utrophils,ALT

,AST,

CRP, D

-dim

er,E

SR,ferritin,IL-8,

LDH,a

ndN-terminal

pro-B

NPin

COVID-19patientswith

diabetes

andhy

perglyc

emia

seco

ndaryvs

.with

out

diabetes

andwith

norm

oglyce

mia

Wan

get

al.

(35)

Wuh

an,China

605

Admission

FBG

$7.0mmol/L

multiv

ariate

HR

2.30

(95%

CI1.49

–3.55

;P5

0.00

02)for

28-day

mortality;

admission

FBG

$7.0an

d6.1–

6.9vs.,6.1mmol/L

OR

3.99

(95%

CI

2.71

–5.88

)an

d2.61

(95%

CI1.64

–4.41

),resp

ectiv

ely,

for28

-day

in-hos

pita

lco

mplications

Hyp

ertens

ionan

dCHD

hadno

sign

ifica

nteffect

on28

-day

mortality;

CKD

and

cerebrova

scular

disea

seha

dun

ivariate

HR

.1for28

-day

mortality

Not

exam

ined

Smith

etal.

(36)

NJ

184

Mos

tpatientsha

ddiabetes

(62.0%

)or

prediabetes

(23.9%

);intubated

patientsha

dhigh

erFB

G(P

50.01

3)an

dHbA1c(P

50.03

4)vs.no

nintub

ated

Mos

tco

mmon

preex

istin

gco

ndition

s:hy

pertens

ion(60.3%

),hy

perlip

idem

ia(33.7%

),dem

entia

(13.0%

),CKD

(13.0%

),CAD

(12.0%

),an

dCHD

(10.9%

);intubated

patientsha

dhigh

erBMI(P

50.03

0)vs.

nonintub

ated

Not

exam

ined

Con

tinue

don

p.25

55


Tab

le1—

Continue

dStudy

Loca

tion

Partic

ipan

ts(n)

Diabetes

find

ings

Com

orbidities

find

ings

*Selec

tlaboratoryfind

ings

**

Sim

onne

tet

al.(39)

Lille,Fran

ce12

4Diabetes

was

notaris

kfactor

inun

ivariate

logistic

regres

sion

analysis

Obes

ity($

35kg

/m2BMI)un

ivariate

OR

6.75

(95%

CI1

.76–

25.85;

P5

0.01

5),m

ultiv

ariate

OR

7.36

(95%

CI1.63

–33

.14;

P5

0.02

1);

hypertens

ionun

ivariate

OR

2.81

(95%

CI

1.25

–6.3;

P5

0.01

2)but

notsign

ifica

ntin

multiv

ariate

analysis;dyslip

idem

iawas

not

aris

kfactor

inun

ivariate

logistic

regres

sion

analysis

Not

exam

ined

Gao

etal.(41)

Wen

zhou

,China

150

Diabetes

morepreva

lent

inob

ese(24.0%

)vs.

nono

bes

e(14.7%

)COVID-19patients

Obes

ityha

dOR

3.00

(95%

CI1.22

–7.38

)after

adjustmen

tforag

e,se

x,sm

okingstatus

,hy

pertens

ion,

diabetes

,dyslip

idem

ia

Eleva

tedCRPan

dlympho

pen

iain

obes

evs.

nono

bes

eCOVID-19patients

Shi

etal.(43)

Wuh

an,China

1,56

1,of

who

m15

3with

diabetes

analyzed

vs.

153ag

e-an

dse

x-match

ed15

3patients

with

out

diabetes

Diabetes

(multiv

ariate

HR

1.58

[95%

CI0.84

–

2.99

])no

tan

indep

enden

tris

kforin-hos

pita

ldea

th;patientswith

diabetes

likelierto

be

admitted

toICU

andex

perienc

eco

mplications

(ACI,AKI,ARDS,etc.)an

ddea

th;no

nsurvivo

rpatientswith

diabetes

likelierto

have

hypertens

ionan

dCVD

(P,

0.05

);hy

pertens

ionmultiv

ariate

HR

3.10

(95%

CI1.14

–8.44

)forin-hos

pita

ldea

thof

patientswith

diabetes

Hyp

ertens

ionmultiv

ariate

HR

2.50

(95%

CI

1.30

–4.78

)an

dCVD

multiv

ariate

HR

2.24

(95%

CI1.19

–4.23

)as

sociated

with

in-hos

pita

ldea

th

Eleva

tedPCTan

dlower

CD81

Tce

llsinpatients

with

diabetes

vs.patientswith

outdiabetes

;elev

ated

gluc

ose,

HbA1c,WBC,ne

utrophils,

Cr,CRP, D

-dim

er,P

CT,

PT,

andlympho

pen

iaan

dlower

eGFR

,CD31

,CD41

,CD81

,CD19

1,an

dCD16

156

1ce

llsin

nons

urvivo

rvs.su

rvivor

patientswith

diabetes

Lassaleet

al.

(40)

U.K.

640COVID-19

hosp

italizations

from

340,96

6registrantsin

UK

Bioban

ksu

bse

tfrom

900COVID-19

hosp

italizations

and42

8,49

4registrants

Diabetes

morepreva

lent

andHbA1chigh

erin

hosp

italized

vs.n

onho

spita

lized

patients(fu

lldatase

t),P,

0.00

1;Lo

gHbA1cremaine

das

sociated

inmultiv

ariate

analysis

(OR

1.60

[95%

CI1

.02–

2.52

];P5

0.04

3;su

b–datase

t);diabetes

morepreva

lent

inBlack

andAsian

patients(fu

lldatase

t)

CVD,hy

pertens

ion,

BMI,WHR

high

eran

dch

oles

terol,HDL-clower

inho

spita

lized

vs.

nonh

ospita

lized

patients(fu

lldatase

t),P,

0.00

1;BMI,WHR,ch

oles

terolrem

aine

dsign

ifica

ntin

multiv

ariate

analysis;Black

patients(OR

2.66

[95%

CI1.82

–3.91

];P,

0.00

1)moresu

scep

tible

toho

spita

lization,

with

adjustmen

tforag

e,se

x,co

morbidities

,an

dso

cioe

cono

mic

factors

Eleva

tedCRPin

hosp

italized

vs.

nonh

ospita

lized

COVID-19patientsbut

did

notremainsign

ifica

ntin

multiv

ariate

analysis

Pric

e-Hay

woo

det

al.(45)

LA3,48

118

.5%

ofBlack

patientsha

ddiabetes

vs.1

0.9%

White.Noan

alysis

perform

edto

disea

sese

verity.

Black

race

was

aho

spita

lizationris

kbut

notan

indep

enden

tin-hos

pita

lmortality

risk

Cha

rlson

Com

orbidity

Index

scoreOR

1.05

(95%

CI1.00

–1.10

)forho

spita

lization

(acc

ountingforrace

,ag

e,se

x,low-inc

ome

area

ofresiden

ce,insu

ranc

eplan,

obes

ity)

but

HR

0.99

(95%

CI0.94

–1.03

)for

in-hos

pita

ldea

th;hy

pertens

ionan

dCKD

morepreva

lent

inBlack

vs.White

patients

Asidefrom

othe

ralte

redmarke

rs,A

ST,

Cr,CRP,

PCT,

andlympho

pen

iaha

dsign

ifica

ntHR.1

forin-hos

pita

ldea

th,afterad

justmen

tfor

race

,ag

e,se

x,co

morbidities

,low-inc

ome

area

ofresiden

ce,an

dlaboratorymea

sures

ALT

,alanine

aminotrans

ferase

;APACHEII,

Acu

tePhy

siolog

yan

dChron

icHea

lthEva

luationII;

BNP,b

rain

natriuretic

peptid

e;CAD,c

oron

aryartery

dise

ase;

CCD,c

hron

icca

rdiacdisea

se;

CFR

,cas

efatalityrate;C

HD,c

oron

aryhe

artd

isea

se;C

K,c

reatinekina

se;C

K-M

B,c

reatinekina

se,m

usclean

dbraintype;

CRP,C

-rea

ctiveprotein;e

GFR

,estim

ated

glom

erular

filtrationrate;

FBG,fas

tingblood

gluc

ose;

HDL-c,

high

-den

sity

lipop

roteinch

oles

terol;IL-6,interleuk

in6;

PT,

prothrombintim

e;T1

D,typ

e1diabetes

;T2D

,typ

e2diabetes

;TT,

thrombintim

e.*C

ondition

sco

morbid

with

diabetes

cons

idered

.**Selec

tlab

oratoryfind

ings

fors

ignifica

ntdifferen

cesreportedin

immun

ece

llpop

ulations

,cytok

ines

,and

biomarke

rsof

infectionan

dkidne

y,liver,a

ndca

rdiacdam

age.

Cha

nges

wererepo

rted

ifthereweresign

ifica

ntdifferen

cesin

either

mea

nva

lues

orin

thenu

mber

ofpa

tientsab

oveacu

toffva

lue.


study (n 5 1,317 participants with diabetes, 88.5% ofwhom had type 2 diabetes) observed that diabetes typeand glycated hemoglobin (HbA1c) level did not affect theprimary outcome in univariate analysis, i.e., tracheal intuba-tion for mechanical ventilation and/or death within 7 days ofadmission (25). Another large study, led by the NationalHealth Service (NHS) England, also focused on both type1 (n 5 364) and type 2 (n 5 7,434) diabetes–associatedCOVID-19 deaths and determined multivariate ORs of2.86 and 1.80, respectively, with adjustment for age, sex,ethnicity, deprivation, CVD, and cerebrovascular disease,though they could not adjust for other frequent comor-bidities, hypertension, chronic kidney disease (CKD), andBMI, due to data set limitations (26). Notably, moststudies have not differentiated diabetes type; CORO-NADO found no differences between type 1 and type2 diabetes in COVID-19 outcomes, but there were only39 patients with type 1 diabetes. In contrast, the NHSEngland study might suggest that patients with type1 diabetes are at greater risk, though this remains tobe validated by additional studies (Fig. 1).

A study from China with 258 COVID-19 patients, of whom63 had diabetes, reported diabetes had a multivariate HR of3.64 for death, with adjustment for age, comorbidities, andinflammatory markers (27). Guo et al. (28) accounted forcomorbidities by comparing mortality in patients without di-abetes (0%) versus with diabetes (16.5%) without comorbid-ities; however, they failed to consider age, which significantlydiffered between groups. In a study of COVID-19 patients withtype 2 diabetes, diabetes led to a higher all-cause mortality of7.8% (vs. 2.7%), with HR 1.49, with adjustment for age, sex,and infection severity (3). These studies of cohorts with

diabetes confirm the concept that persons with diabeteswho contract COVID-19 disease have poorer outcomes.

Glycemic Control and Elevated Fasting Blood GlucoseWell-controlled blood glucose has emerged as an importantoutcome parameter and conferred lower mortality (HR 0.14)in a propensity score–matching model that accounted for age,sex, comorbidities, and several additional parameters (3). Thisfinding agrees with other studies that identified diabetes and/or uncontrolled or variable hyperglycemia at admission(29,30), ICU admission (31), or during in-hospital stay (32)as a severe disease or mortality risk. In the large U.K. Open-SAFELY study of 10,926 COVID-19 deaths in comparisonwitha database of 17,278,392 adults, greater mortality occurredwith poorer glycemic control (stratified by HbA1c) (4). Patientswith diabetes with HbA1c ,7.5% had a fully adjusted HR of1.31 for death, whereas HR was 1.95 with HbA1c $7.5%.These findings were mirrored by the NHS England study inboth patients with type 1 diabetes (HbA1c $10.0%, HR 2.23)and patients with type 2 diabetes (HbA1c 7.5–8.9%, HR 1.22;HbA1c 9.0–9.9%, HR 1.36; and HbA1c$10.0%, HR 1.61) (33).

COVID-19 can also induce hyperglycemia in patientswithout diabetes, secondary to infection, which increasesthe risk of critical disease (34,35). Finally, prediabetes,characterized by elevated fasting blood glucose or impairedinsulin sensitivity, has been mostly overlooked in COVID-19 studies but could nevertheless pose a threat to clinicaloutcomes (Fig. 1). In a U.S. study of 184 patients, most haddiabetes (62.0%) or prediabetes (23.9%), and stratifyingpatients solely by elevated fasting blood glucose or HbA1cincreased the risk of intubation (36). A China study alsofound that elevated fasting blood glucose (.7.54 mmolcutoff) independently predicted mortality (HR 1.19) (27).

Figure 2—Illustration of parallels in acute COVID-19 pathology versus chronic diabetes pathology. COVID-19 infection induces acuteinflammatory cytokine storm, hyperglycemic surges, and acute organ damage. Diabetes is characterized by chronic, low-grade inflammation,glucose variability, and slowly progressing tissue damage in microvascular (CKD, neuropathy, brain) and macrovascular (CVD) complications.Additional shared detrimental mechanisms include hypercoagulation, endothelial dysfunction, and fibrosis. Drawn in part with BioRender.


Overall, there is a consensus from clinical studies andmeta-analyses (36 and reviewed in 37) that diabetes isa risk factor for serious COVID-19 infection and mortality,though this dependency may be less significant by multi-variate analysis in some studies. Varying study results arelikely due to the fact that many, but not all, patients withdiabetes suffer from additional comorbidities, such asobesity, hypertension, and CVD, which are independentrisk factors (Fig. 1).

Comorbidities and COVID-19

Comorbidities in General COVID-19 Patient CohortsObesity (19,20,25,39–41), CKD (19,20), CVD (5,20), andhypertension (20) persist as risk factors for hospitalizationor serious COVID-19 disease in multivariate analysis insome studies, after adjustment for various clinical varia-bles (Table 1 and Fig. 1), and in meta-analyses (37). Ina French cohort (n 5 124), obesity (BMI $35 kg/m2), butnot diabetes, was a strong predictor for mechanical ven-tilation use, with multivariate OR 7.36, after adjustmentfor age, sex, diabetes, and hypertension (39). The Open-SAFELY study reported that mortality risk increased withBMI, with HR 1.40 for class II obesity (BMI 35–39.9 kg/m2) and HR 1.92 for class III obesity (BMI$40 kg/m2) (4).This was similar to a NYC study, where BMI proportion-ately increased hospitalization risk (20). In a China cohort(n5 150), obesity was an independent predictor of seriousinfection (multivariate OR 3.0) and obese patients werelikelier to have diabetes versus other age- and sex-matchedCOVID-19 patients, underscoring the frequent occurrenceof comorbidities in patients with diabetes (41). Surpris-ingly, obesity with BMI $40 kg/m2 was not a risk forin-hospital mortality in a NYC cohort (5).

There are fewer reports on comorbid dyslipidemia. Themost comprehensive analysis leveraged data from the UKBiobank as a control population (n 5 428,494) versushospitalized COVID-19 patients (n 5 900) (40). Diabetes,HbA1c, CVD, hypertension, BMI, and waist-hip-ratio (WHR)were higher and cholesterol and HDL cholesterol lower inCOVID-19 patients. Log(HbA1c), BMI, and WHR (OR . 1)and total cholesterol (OR , 1) remained significant inmultivariate analysis in a subset of 340,966 UK Biobankregistrants vs. 640 COVID-19 hospitalized patients. Finally,LDL did not vary significantly between patients with diabeteswith poorly or well-controlled glucose (3) and was protectivefrom ARDS (HR 0.63) but not death (22).

Comorbidities in Cohorts of Patients With COVID-19 andDiabetesPatients with diabetes frequently suffer from comorbid-ities, e.g., obesity, dyslipidemia, hypertension, CVD, andCKD (42), which would predispose them to poorer COVID-19 outcomes. In mostly CORONADO participants withtype 2 diabetes, obesity by BMI positively predicted thestudy primary outcome, with OR 1.28 (i.e., tracheal in-tubation and/or death within 7 days of admission) (25).Dyslipidemia, although present in 51.0% of patients, did

not significantly increase risk of the composite primaryoutcome (25). In a second NHS England study, those whodied from COVID-19 (type 1 diabetes, n 5 464; type2 diabetes, n 5 10,525) were compared with individualswith diabetes registered to a practice (type 1, n5 264,390;type 2, n 5 2,874,020) to identify mortality risk factors(33). Type 1 diabetes shared the same risks as type 2 di-abetes for COVID-19 mortality, with preexisting CVD,CKD, and obesity identified as independent factors. Onestudy, with COVID-19 patients with diabetes (n5 153) ageand sex matched to 153 COVID-19 patients without di-abetes reported that CVD and hypertension were inde-pendent risk factors for mortality risks among all patients(43). These studies support the idea that comorbidities inpatients with diabetes, independent of diabetes itself,increase adverse COVID-19 disease outcomes.

Cumulative Comorbidities EffectFurthermore, COVID-19 patients with more than one comor-bidity may be especially vulnerable. In NYC, COVID-19patients were far likelier to have two or more comorbidities,constituting 88% of hospital admissions versus admissions ofpatientswith only one comorbidity (6.3%) or no comorbidities(6.1%) (17). In a nationwide study in China (n 5 1,590), theHR was 1.79 for one comorbidity and as high as 2.59 for twoor more comorbidities after adjustment for age and smokingstatus (44). When the data from this cohort were used todevelop a scoring system to predict serious clinical trajectoriesfrom admission status, the number of comorbidities (OR1.60) emerged as 1 of 10 variables (24). The CharlsonComorbidity Index, a score based on the presence of comor-bidities from a list that includes diabetes and kidney andcardiac diseases, had a multivariate OR of 1.05 for hospital-ization but an HR of only 0.99 for in-hospital death (45).

Overall, in assessment of risk for a COVID-19 patientwith diabetes at admission, overall comorbidities, includ-ing degree of glucose control (assessed by HbA1c [36,40]),fasting blood glucose (36), obesity (19,25,39,40), and thenumber of additional comorbid conditions, will be impor-tant clinical parameters to consider (Fig. 1).

Pediatric Diabetes and Comorbidities in COVID-19Fortunately, there is agreement to date that most pediatricCOVID-19 patients present with asymptotic or mild dis-ease (46). Nevertheless, some children suffer from moreserious COVID-19 infection, requiring hospitalization andeven pediatric ICU (PICU) (Table 2). The reasons forserious illness remain incompletely understood; however,drawing a parallel to adults, the presence of comorbidities,which are less frequent in young patients, may be onereason fewer children are vulnerable to COVID-19 but whysome still fall critically ill. Given the recent rise in type2 diabetes and obesity in youth, there could be a significantnumber of children at risk. Unfortunately, the few studiesthat have examined diabetes and other comorbidities inchildren with COVID-19 are relatively small, making ithard to draw conclusions.


Tab

le2—

Ove

rview

ofped

iatric

andpregna

ncyCOVID

-19clinical

coho

rts

Study

Loca

tion

Partic

ipan

ts(n)

Diabetes

find

ings

Com

orbidities

find

ings*

Selec

tlaboratoryfind

ings

**

She

kerdem

ian

etal.(47)

U.S.,Can

ada

48ped

iatric

patientsad

mitted

toPICUs

8%ha

ddiab

etes

83%

hadsign

ifica

ntco

morbidities

:15

%wereob

ese,

6%ha

dco

ngen

italh

eart

dise

ase

Not

exam

ined

Cha

oet

al.(48)

NYC

21ped

iatric

outpatients,

33to

GPMU,13

toPICU

Diabe

tesno

tedin

critica

lillnes

s(3

of13

)but

notsign

ifica

ntly

correlated

toPICU

Obes

itypreva

lent

incritica

lillnes

s(3

of13

)but

notsign

ifica

ntly

correlated

toPICU

Lower

ASTan

delev

ated

CRP,

PCT,

andpro-B

NPin

PICU

vs.

non-PICU

patie

nts

Zac

haria

het

al.(49)

NYC

50ho

spita

lized

ped

iatric

patients

Diabe

tesdid

notraisetheris

kof

seve

redise

ase,

but

fewpatients

haddiabetes

(n5

3)

Significa

ntly

morepatientswereob

ese

with

seve

re(67%

)vs.

nons

evere(20%

)COVID-19(P

50.03

)

Eleva

tedCRPan

dPCTin

seve

revs

.no

nsev

ereCOVID-19

Ottoet

al.(50)

U.S.

424patientsag

e0–

21ye

ars,of

who

m77

wereho

spita

lized

Diabe

tesno

tedinfreq

uently

13%

ofallp

atientswereob

ese

Not

exam

ined

Ebek

ozienet

al.(51)

U.S.

33COVID-19pos

itive

,31

COVID-19–

likeT1

Dped

iatric

andad

ultpa

tients

Hyp

erglyc

emia

andDKAwere

common

adve

rseou

tcom

esObes

itywas

preva

lent;CVD,

hypertens

ion,

hyperlip

idem

iaalso

pres

ent

Not

exam

ined

Sen

tilhe

set

al.(52)

Fran

ce54

pregn

antfemales

Onlyfour

hadge

stationa

ldiabetes

mellitus

;sa

mple

size

toosm

all

foran

ypoten

tiallinkto

COVID-

19

Obes

itymay

bearis

k;on

lytw

oha

dge

stationa

lhyp

ertens

ion;

samplesize

toosm

allfor

anypoten

tiallinkto

COVID-19

Eleva

tedALT

,AST,

CRP,an

dlympho

pen

iain

hosp

italized

COVID-19pa

tients

Lokk

enet

al.(53)

WA

46pregn

antfemales

Onlyon

eha

dge

stationa

ldiabetes

mellitus

;sa

mple

size

toosm

all

foran

ypoten

tiallinkto

COVID-

19

26.1%

hadan

underlyingco

ndition

;two-

third

swereov

erweigh

t(28

.6%

,n5

12)

orob

ese(35.7%

,n5

15)by

prep

regn

ancy

BMI;15

%dev

elop

edse

vere

disea

se,of

who

m80

%were

overweigh

tor

obes

eby

prepregn

ancy

BMI;on

lytw

oha

dge

stationa

lhy

pertens

ion;

samplesize

toosm

allfor

anypoten

tiallinkto

COVID-19

Not

exam

ined

atpo

pulationleve

l

Knigh

tet

al.(54)

U.K.

427pregn

antfemales

3%ha

ddiab

etes

,12

%ha

dge

stationa

ldiabetes

mellitus

,;no

analysis

performed

for

disea

sese

verity

35%

overweigh

t,34

%ob

ese,

34%

pree

xistingco

morbidities

;no

analysis

performed

fordisea

sese

verity

Not

exam

ined

Kay

emet

al.(55)

Fran

ce61

7pregn

antfemales

Preex

istin

gdiabetes

(2.3%

preva

lenc

ein

totalp

opulation)

raised

theris

kof

seve

redise

ase,

RR

3.8(95%

CI1.4–

10.7),but

notg

estatio

naldiabe

tesmellitus

(11.5%

prev

alen

ce)

BMI(RR

1.9[95%

CI1.4–

2.5]),

hypertens

ion,

gestationa

lhyp

ertens

ion

orpreec

lamps

iaweremoreco

mmon

inse

vere

disea

se

Not

exam

ined

ALT

,alanine

aminotrans

ferase

;BNP,b

rainna

triuretic

pep

tide;

CRP,C

-rea

ctiveprotein;D

KA,d

iabeticke

toac

idos

is;G

PMU,g

eneralped

iatricmed

icalun

it;T1

D,typ

e1diabe

tes.*C

ondition

sco

morbid

with

diabetes

cons

idered

.**Selec

tlab

oratoryfind

ings

fors

ignifica

ntdifferen

cesreportedin

immun

ece

llpop

ulations

,cytok

ines

,and

biomarke

rsof

infectionan

dkidne

y,liver,a

ndca

rdiacdam

age.

Cha

nges

wererepo

rted

ifthereweresign

ifica

ntdifferen

cesin

either

mea

nva

lues

orin

thenu

mber

ofpa

tientsab

oveacu

toffva

lue.


A cross-sectional study of 48 pediatric patients (0–21years old), admitted to PICUs across the U.S. and Canada,found 83% had significant comorbidities: 15% were obese,8% had diabetes, and 6% had congenital heart disease (47). Achildren’s hospital in NYC (n 5 67, aged 1 month–21 years)admitted 13 patients to PICU, noting the presence of bothdiabetes (3 of 13) and obesity (3 of 13) but not to significance;however, the cohort was small (48). Another study (n 5 50,aged 6 days–21 years) at a different NYC children’s tertiarycare center found significantly more obesity in severe (67%)versus nonsevere (20%) COVID-19, but not diabetes, possiblydue to the small number of patients with diabetes (n 5 3)(49). Obesity is a recurrent theme and was relatively prev-alent in other pediatric studies also (50,51).

The cumulative evidence from pediatric studies sug-gests that comorbidities may be a predisposing factor forserious COVID-19 infection in children, particularly obe-sity. The impact of diabetes remains unclear due to rela-tively low study participant numbers (Fig. 1).

Pregnancy, Diabetes, and Comorbidities in COVID-19Pregnancy is a vulnerable period, particularly since gesta-tional diabetes mellitus may develop; yet, few studies haveexamined pregnant women admitted for COVID-19 infec-tion (Table 2). A French cohort of 54 pregnant women withsuspected or confirmed COVID-19 included four patientswith gestational diabetes mellitus and two with gestationalhypertension, which were too few to analyze for a potentiallink to infection severity (52). However, prepregnancy over-weight or obese BMI were relatively prevalent, which theauthors concluded could be a risk factor for COVID-19disease. Another small study (n 5 46), in the U.S., alsofound a high prevalence of elevated prepregnancy BMI(28.6%, overweight, and 35.7%, obese) (53). Moreover,15% of pregnant patients developed severe infection, ofwhom 80% were overweight or obese. A U.K. study of427 pregnant women with confirmed COVID-19 drewsimilar observations, finding that 35% of patients wereoverweight and 34% were obese (54). The diabetes preva-lence was 3%, whereas it was 12% for gestational diabetesmellitus, but no analysis of disease severity was performed.

The largest study to date was in 617 pregnant Frenchwomen (55). Preexisting diabetes was present in 2.3% of thetotal population and raised the chance of severe disease, witha risk ratio (RR) of 3.8. In contrast, gestational diabetesmellitus, at 11.5% prevalence, did not affect outcomes forinfection severity. The investigators did not discuss reasons forthe difference in risk from preexisting diabetes versus gesta-tional diabetes mellitus, but it raises the question of whethergestational diabetes mellitus interacts distinctly with COVID-19 pathophysiology (Fig. 1). Diabetes complications, for in-stance, from preexisting diabetes, could be a factor for seriousinfection, which draws parallels to studies of general popula-tions with diabetes (25). The study also found that BMI has anRR of 1.9, hypertension an RR of 2.4, and gestational hyper-tension or preeclampsia an RR of 2.4 for severe COVID-19,though the latter two did not reach significance.

Collectively, the data from pregnancy cohorts echofindings from adult studies, with diabetes, obesity, andcomorbidities likely predisposing to poorer outcomes.However, it is possible that gestational diabetes mellitusmay not be a factor, though larger studies are needed for usto definitively conclude this.

Race, Diabetes, and Comorbidities in COVID-19Race disparities are an emergent theme during the COVID-19 pandemic (Table 3). The precise reasons to date remainunclear, though the prevalence of comorbidities, includingobesity, (56) and socioeconomic factors (57) have beensuggested. Of the U.S. population, 18% are Hispanic, 13%Black, and 0.7% American Indian or Alaska Native; yet,these groups have disproportionately constituted 33%,22%, and 1.3%, respectively, of adult U.S. COVID-19 cases(58) and are also highly represented in hospitalized pedi-atric patients (50).

Several observational studies have taken a more de-tailed look to understand these racial disparities. InDetroit cohorts, Black race did not increase risk of severeinfection (19,59); however, diabetes or comorbidities prev-alence by race was not examined (19). These findings partlyagree with those of a Georgia study (n5 297), which foundthat although hospitalizations among Black patients(83.2%) were disproportionate to numbers among otherraces, indicating greater disease severity, Black patients didnot have higher mechanical ventilation use or mortality (60).This study also reported the prevalence of comorbidities,which did not differ significantly for diabetes in Black versusother races but did differ for hypertension and mean BMI. Alarger Louisiana cohort (n 5 3,481) similarly concluded thatBlack race was a hospitalization risk but not an independentin-hospital mortality risk (45). Although the investigatorsfound diabetes, hypertension, and CKD prevalence to behigher in Black versus White patients, they did not performan analysis for disease severity. A California study (n 51,052) analyzed hospitalization risk for Black, Asian, andHispanic race relative toWhite, but only Black race had anOR2.7, after adjustment for sex, age, comorbidities, and socio-economic factors (57). U.K. studies have also noted greatersusceptibility of Black patients, and other race minorities, toCOVID-19 disease (61) and hospitalization (40), after ad-justment for several cardiometabolic and socioeconomicfactors. Strikingly, a NYC study found that Black race wasprotective for critical illness and death, whereas Hispanic racewas a risk for hospitalization (20).

Importantly, some studies have reported increased mor-tality risk for Black race and other minorities. Analysis of NYCdemographics and COVID-19 deaths (n5 4,260) revealed thatHispanic (22.8%) and Black (19.8%) patients had the highestage-adjusted mortality per 100,000, which corresponded tothe highest obesity rates: 25.7% and 35.4%, respectively (56).However, the study did not adjust for other importantvariables. Lacking complete U.S. nationwide disaggregateddata by race, Millett et al. (62) analyzed county-level de-mographics and COVID-19 deaths. Counties with a greater


Tab

le3—

Ove

rview

ofCOVID

-19clinical

coho

rtswithinve

stigationofsu

scep

tibility

byrace

andethn

icity

Study

Loca

tion

Partic

ipan

ts(n)

Diabetes

find

ings

Com

orbidities

find

ings

*Selec

tlaboratoryfind

ings

**

Stoke

set

al.(58)

U.S.

599,63

6of

know

nrace

Noco

rrelationstud

yof

diabetes

torace

perform

ed33

%Hispan

ic,2

2%Black

,1.3%

American

Indianor

Alask

aNative,

which

acco

unt

for18

%,13

%,an

d0.7%

oftheU.S.

population,

resp

ectiv

ely,

sugg

estin

gthey

weredisprop

ortio

natelyaffected

byCOVID-19

Not

exam

ined

Bha

rgav

aet

al.(59)

Detroit,

MI

197

Diabetes

morefreq

uent

inpatientswith

seve

re(48.6%

)vs

.no

nsev

ereinfection

(30.1%

),OR

2.20

(95%

CI1

.21–

4.0;

P5

0.00

9)in

univariate

analysis

butno

tmultiv

ariate;no

correlationstud

yof

diabetes

torace

performed

Obes

ity,hy

pertens

ion,

cong

estiv

ehe

art

failure,ce

rebrova

scular

disea

sedid

not

increa

seun

ivariate

ORof

seve

redisea

se,

thou

ghCKDdid;8

2.1%

wereBlack

,and

Black

race

was

notaris

kforse

vere

infection

Eleva

tedCran

dPCTha

dsign

ifica

ntun

ivariate

OR.1for

seve

redisea

se;elev

ated

Cr

from

bas

elinean

dinitial

CRP

hadsign

ifica

ntmultiv

ariate

OR

.1forse

vere

infection

Goldet

al.(60)

GA

297;

Black

hosp

italizations

(83.2%

)were

disproportio

nate

toothe

rrace

s,indicatinggrea

ter

disea

sese

verity

Diabetes

prev

alen

cedid

notdiffer

sign

ifica

ntly

inBlack

patients(41.7%

)vs

.inpatientsof

othe

rrac

es(32.0%

)P5

0.21

Hyp

ertens

ionmoreco

mmon

inBlack

patie

nts(69.6%

)vs

.patientsof

othe

rrace

s(54.0%

),P5

0.04

7;mea

nBMI

high

erin

Black

(31.4%

)patientsvs

.pa

tientsof

othe

rrace

s(29.6%

),P5

0.00

3;Black

patientsdid

noth

avehigh

ermec

hanica

lven

tilationus

eor

mortality

Not

exam

ined

Aza

ret

al.(57)

CA

1,05

2co

nfirm

edca

ses

Diabetes

hadOR2.2,

P,

0.01

,forho

spita

lad

mission

,in

multiv

ariate

analysis

with

adjustmen

tforse

x,ag

e,co

morbidities

,so

cioe

cono

mic

factors;

noco

rrelation

stud

yof

diabetes

torace

perform

ed

Non

-Hispan

icAfrican

American

sha

dOR

2.7,

P5

0.00

7,forh

ospita

ladmission

vs.

non-Hispan

icWhites,

afterad

justmen

tforthesa

meva

riablesas

listedfor

diab

etes

find

ings

Not

exam

ined

Raisi-Estab

ragh

etal.(61)

U.K.

1,32

6pos

itive

,3,18

4ne

gativ

eCOVID-19tests

from

UKBioban

k

Diabetes

notaris

kforsu

scep

tibility

topos

itive

vs.ne

gativ

eCOVID-19test;no

correlationstud

yof

diabetes

torace

perform

ed

Hyp

ertens

ion,

high

choles

teroln

otris

ksfor

susc

eptib

ility

topos

itive

vs.ne

gativ

eCOVID-19test;Black

,Asian

,an

dminority

ethn

icgrou

pmoresu

scep

tible

topo

sitiv

evs

.ne

gativ

eCOVID-19test,

with

adjustmen

tforag

e,se

x,BMI,

diab

etes

,hy

pertens

ion,

choles

terol,an

dso

cioe

cono

mic

factors

Not

exam

ined

ElC

haar

etal.(56)

NYC

4,26

0de

aths

Diabetes

notinve

stigated

Hispa

nican

dBlack

patie

ntsha

dhigh

est

age-ad

justed

mortalityratesper

100,00

0(22.8%

and19

.8%

,resp

ectiv

ely,

vs.

othe

rethn

icgrou

ps)

corres

pon

dingto

thegrou

pswith

thehigh

esto

bes

ityrates,

25.7%

and35

.4%

,resp

ectiv

ely,

P,

0.05

;the

twoNYCborou

ghswith

high

est

mortalityrates,

Bronx

(6%

)and

Brook

lyn

(5.4%

),also

hadthehigh

estob

esity

rates,

32%

and27

%,resp

ectiv

ely

Not

exam

ined

Con

tinue

don

p.25

61


proportion of Black residents (i.e., above national average,$13%) hadmore COVID-19 cases (rate ratio 1.24) and deaths(rate ratio 1.18), after adjustment for county-level traits, e.g.,age, comorbidities, poverty, and pandemic duration. Diabetesprevalence was also higher (13.9% vs. 11.1%) in counties withhigh ($13%) and low (,13%) proportion of Black residentsbut did not correlate with COVID-19 cases (rate ratio 0.97) ordeaths (nonsignificant rate ratio 1.01), after adjustment fordemographics, comorbidities, and socioeconomic factors.Thus, diabetes, or other cardiometabolic effects, may not besolely attributable to COVID-19 risk in Black patients. Finally,large population-based studies, OpenSAFELY and NHSEngland, found higher mortality risk for Asian and Blackraces, after adjustment for age, sex, comorbidities, andsocioeconomic status (4,26,33).

Overall, Black, Hispanic, and possibly other races may berisk factors for serious COVID-19 infection or death, but thefactors driving this disparity are presently unclear (Fig. 1).

COVID-19 and Diabetes Pathology: Collision andCollusionGiven the relatively short time that has elapsed since theSARS-CoV-2 pandemic broke out, its pathophysiology remainsincompletely understood. However, like its predecessorsSARS-CoV and Middle East respiratory syndrome corona-virus (MERS-CoV), SARS-CoV-2 gains cellular entry byleveraging the ACE2 receptor, a master regulator of therenin-angiotensin system. The major viral spike glycopro-tein (S1) binds to ACE2 (63), while proximal serine pro-teases, like the transmembrane serine protease 2, cleave thevirus spike protein and ACE2, promoting viral internalization(64). Infection induces cell death, which triggers inflamma-tory cytokine production and inflammatory immune cellrecruitment (65). SARS-CoV-2 also infects circulating im-mune cells, stimulating lymphocyte apoptosis and inflam-matory cytokine secretion, known as “cytokine storm” (6).High circulating cytokine levels contribute to SARS-CoV-2–driven multiorgan failure and disrupted endocrine signalingand hyperglycemia surges (66). Widespreadmultitissue ACE2expression, e.g., lung, heart, kidney, and nerve (67), leads totropism, as validated by viral detection within multipletissues (7,68). Tropism potentially constitutes another path-way to multiorgan damage in COVID-19 patients, e.g., acutecardiac injury (ACI) and acute kidney injury (AKI) (13,14).

Although the inflammatory, hyperglycemic, and tissuedamage response is intensely acute in COVID-19 infection,it is mirrored by diabetes pathology (Fig. 2), which ischaracterized by chronic, low-grade inflammation, im-paired glycemic control, and slowly progressive multitissueinjury, e.g., diabetic microvascular (CKD, neuropathy,brain) and macrovascular (CVD) complications (8,69).Although the underlying reasons for the susceptibilityof patients with diabetes to COVID-19 remain unclear,commonalities in pathology suggest that acute COVID-19–induced adverse reactions may superimpose on preexistinginflammation, glucose variability, and multitissue injury inpatients with diabetes to aggravate outcomes (Fig. 1).

Tab

le3—

Continue

d

Study

Loca

tion

Partic

ipan

ts(n)

Diabetes

find

ings

Com

orbidities

find

ings

*Selec

tlaboratoryfind

ings

**

Millet

etal.(62)

U.S.

Nationw

idepop

ulation

dem

ographics

andCOVID-

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ths

Diabetes

preva

lenc

ein

coun

tieswith

,13

%Black

residen

tswas

11.1%

vs.13

.9%

inco

untie

swith

$13

%Black

residen

ts,P

valueno

tstated

;diabetes

preva

lenc

edid

notco

rrelatewith

coun

tiesby

COVID-19

case

s(ra

teratio

0.97

[95%

CI0

.92–

1.03

])or

dea

ths(ra

teratio

1.01

[95%

CI0.88

–

1.16

]),afterad

justmen

tfordem

ographics

,co

morbidities

,and

socioe

cono

mic

factors

Cou

ntieswith

high

erBlack

residen

tprop

ortio

ns($

13%

)had

moreCOVID-19

case

s(ra

teratio

1.24

,95%

CI1

.17–

1.33

)an

ddea

ths(ra

teratio

1.18

,95%

CI1

.00–

1.40

),afterad

justingforco

unty-lev

eltraits,e.g.,ag

e,co

morbidities

,po

verty,

andep

idem

icdu

ratio

n

Not

exam

ined

*Con

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morbidwith

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tesco

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ignifica

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mun

ece

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ulations

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ines

,and

biomarke

rsof

infectionan

dkidne

y,liver,an

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age.

Cha

nges

werereportedifthereweresign

ifica

ntdifferen

cesin

either

mea

nva

lues

orin

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mber

ofpatientsab

oveacu

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Do Preexisting Diabetes Complications PredisposePatients to Acute COVID-19–Induced Organ Damage?Few studies have stratified COVID-19 patients by diabetesstatus to examine the possibility that preexisting micro-and macrovascular complications render patients suscep-tible to acute organ injury (Fig. 1). CORONADO (n 5 1,317)demonstrated that preexisting microvascular (OR 2.14) andmacrovascular (OR 2.54) complications independently associ-ated with 7-day mortality (25), suggesting that the presence ofdiabetes complications may set patients on poorer clinicaltrajectories. In a NYC study of 5,449 severe COVID-19patients, of whom 1,993 developed AKI, diabetes was a riskfor renal damage, with 41.6% developing AKI vs. 28.0% whodid not (70). Diabetes also correlated with progressive damagein AKI stage 1 (39.7%), stage 2 (43.2%), and stage 3 (43.5%) byKidney Disease: Improving Global Outcomes (KDIGO) criteria.After adjustment for age, sex, and race, diabetes had an OR of1.76 for AKI. However, the study did not state whether AKIcorrelated with preexisting CKD, since baseline CKD data werenot available, although associations with preexisting CKD andAKI have been noted in meta-analysis (71).

Although diabetes was not an independent risk for COVID-19 death in a cohort of 153 patients with diabetes comparedwith age- and sex-matched individuals without diabetes,patients with diabetes were more likely to have preexistingCVD and be admitted to ICUs and experience acute complica-tions (ACI, AKI, ARDS) (43). Nonsurvivor patients with diabeteshad higher blood glucose levels and a greater chance of ACI orAKI, in addition to an altered inflammatory and immune systemprofile (see Are Patients With Diabetes Predisposed to AcuteCOVID-19–Induced Inflammatory Response?).Within a cohortwith diabetes (n5 952), patients with well-controlled glucosewere also less likely to suffer from hypertension and CVD.They were also at lowered risk of AKI (HR 0.12) and ACI(HR 0.24), after adjustment for comorbidities (3), indicat-ing that even if preexisting microvascular complicationscontribute to acute organ injury, additional factors, suchas glucose control or inflammation, may also participate.

Additional Aspects of COVID-19 Tropism Relevant toDiabetesOne particular aspect of COVID-19 tropism meriting closeattention from a diabetes perspective is the possibility ofincreasing the incidence of b-islet damage–induced type1 diabetes. Drawing parallels, SARS-CoV may have beenresponsible for acute type 1 diabetes onset by leveragingb-islet ACE2 expression to induce loss of islets (72). It ispossible that COVID-19 might also trigger acute-onset type1 diabetes in individuals predisposed to autoimmunity (73).Indeed, the multicenter regional data from North WestLondon just reported an 80% increase in new-onset type1 diabetes cases and diabetic ketoacidosis in children up tothe age of 16 years during the COVID-19 pandemic peak (74).Moreover, COVID-19 tropism through ACE2 expression inadipose tissue may underlie the link to obesity as a seriousinfection risk, since adipose tissue could potentially serve asa reservoir of viral shedding (75).

Are Patients With Diabetes Predisposed to AcuteCOVID-19–Induced Inflammatory Response?Although the full cytokine storm profile in COVID-19 is notfully characterized yet, hyperinflammation predicts seriousdisease (Fig. 1). Lymphopenia along with elevation in whiteblood cells (WBC), neutrophils, C-reactive protein (CRP),erythrocyte sedimentation (ESR), ferritin, IL-6, and procalci-tonin (PCT) associates with poorer COVID-19 clinical course,defined as serious infection, ARDS, ICU admission, or death,in studies in multiple countries (Table 1). COVID-19 patientsexperience, in parallel to inflammation, elevated AST, brainnatriuretic peptide, hypersensitive troponin I (hs-TnI), cre-atine kinase (muscle and brain type), lactate dehydrogenase(LDH), and creatinine (Cr), indicative of tissue damage.Clotting homeostasis is similarly compromised, e.g., withelevated D-dimer with longer thrombin or prothrombintime, which also correlate with clinical progression. Ameta-analysis found higher AST (.40 units/L), Cr ($133mmol/L), D-dimer (.0.5 mg/L), hs-TnI (.28 pg/mL), LDH(.245 units/L), and PCT (.0.5 ng/mL) and lower WBC(,4 3 109 per L) defines an OR .1 for critical illness (76).

Diabetes is also characterized by chronic, low-gradeinflammation, which is also a prominent feature of itscomplications, diabetic CKD, CVD, and neuropathy(8,77,78). Several proinflammatory molecules from theCOVID-19 cytokine storm cascade are shared with type2 diabetes pathophysiology, such as CRP, IL-6 (77), andPCT (79). The underlying chronic inflammatory state indiabetes may be “locked and loaded” for virus-induceddamage, promoting a vicious cycle of cytokine releaseand hyperglycemic surges, leading to more widespreadmultiorgan damage, including injury to tissues alreadyweakened by preexisting diabetes complications.

Worryingly for patients with diabetes, and as an addedlayer of risk, they are more prone to cytokine storm, whichpredicts poorer outcomes (Table 1). Admission CRP (OR1.93) and AST (OR 2.23) independently predicted 7-daymortality in the CORONADO COVID-19 patients withdiabetes (25). In Chinese cohorts, patients with diabeteshad a more inflammatory profile than patients withoutdiabetes (3,27). More favorable inflammatory and tissuebiomarker profiles were also evident in patients with type2 diabetes with well-controlled versus poorly controlledblood glucose (3,30). Another study found differences innumerous inflammation and organ damage biomarkers innonsurviving versus surviving patients with diabetes,which also correlated with glucose and HbA1c levels(43). Moreover, elevated inflammation and organ damagebiomarkers were present in COVID-19 patients with di-abetes and hyperglycemia secondary versus without di-abetes and with normoglycemia (34).

One inflammatory biomarker, with deep roots in di-abetes pathophysiology, not widely investigated in COVID-19, is soluble urokinase-type plasminogen activator re-ceptor (suPAR). In Greek (n 5 57) and U.S. (n 5 21)COVID-19 cohorts, we found that admission suPAR pre-dicted severe respiratory failure (80). suPAR correlates


with diabetes risk (81) and reflects the underlying chronicinflammatory process of its micro- (82) and macrovascularcomplications (83).

The reasons for the susceptibility of patients withdiabetes to COVID-19 are multifaceted and reflect thecomplex pathophysiology of both diabetes and COVID-19 infection. Diabetes and its comorbidities, inflamma-tion, glucose variability, and other factors, may “collide andcollude” to disproportionally set COVID-19 patients withdiabetes on poorer clinical trajectories (Fig. 2).

Diabetes and COVID-19 SequelaeIt is becoming clear that COVID-19 survivors suffer frompersistent symptoms (84) and may also face a lifetime ofsequelae, which draws parallels to SARS-CoV and MERS-CoV(10,85). Although the pandemic has not yet lasted longenough to measure long-term outcomes, the evidence todate suggests a significant burden of possibly irreversiblenew complications. For instance, COVID-19, like SARS-CoVand MERS-CoV, may aggravate preexisting CVD or eveninduce new cardiac pathology (86), including in patientswith type 2 diabetes (87). COVID-19 patients with preexist-ing CKD are likelier to suffer AKI (71). COVID-19 also elicitsneurological manifestations (88) and cognitive impairment(89), which exhibit shared pathology with diabetes throughcytokine storm, hypercoagulability, and endothelial d

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