Rapid Communication

doi: 10.1111/joim.13156

COVID-19 retinal microangiopathy as an in vivo biomarker of

systemic vascular disease?
M. F. Landecho1,2 , J. R. Yuste1,2,3, E. Gandara4, P. Sunsundegui1,2, J. Quiroga1,2,5, A. B. Alcaide1,6 &
A. Garcıa-Layana4
From the 1Covid19 Department, Clinica Universidad de Navarra, Pamplona, Navarra, Spain; 2Internal Medicine Department, Clinica
Universidad de Navarra, Pamplona, Navarra, Spain; 3Microbiology and Infectious Diseases Division, Clinica Universidad de Navarra,
Pamplona, Navarra, Spain; 4Ophtalmology Department, Clinica Universidad de Navarra, Pamplona, Navarra, Spain; 5CIBEREHD; and
6
Pulmonary Medicine Department, Clinica Universidad de Navarra, Pamplona, Navarra, Spain

Abstract. Landecho MF, Yuste JR, G andara E,
Sunsundegui P, Quiroga J, Alcaide AB, Garcıa-
Layana A (Clinica Universidad de Navarra,
Pamplona, Navarra; Clinica Universidad de
Navarra, Pamplona, Navarra; Clinica Universidad
de Navarra, Pamplona, Navarra; Clinica Universidad
de Navarra, Pamplona, Navarra; CIBEREHD; and
Clinica Universidad de Navarra, Pamplona, Navarra,
Spain). COVID-19 retinal microangiopathy as an
in vivo biomarker of systemic vascular disease?
(Rapid Communication). J Intern Med, 2020;
https://doiorg/10.1111/joim.13156
Importance. COVID-19 is caused by SARS-CoV-2, a
betacoronavirus that uses the angiotensin-convert-
ing enzyme-related carboxypeptidase (ACE2)
receptor to gain entry into cells. ACE2 receptor is
widely expressed in multiple organs, including the
retina, an extension of the central nervous system.
The ACE2 receptor is involved in the diabetic and
hypertensive retinopathy. Additionally, coron-
aviruses cause ocular infections in animals,
including retinitis, and optic neuritis.
Objective. To assess whether there is any retinal
disease associated with COVID-19.
Design. We have evaluated 27 asymptomatic sub-
jects, with retinal fundoscopic, optical coherence
tomography (OCT) and OCT angiography fourteen
days after hospital discharge due to COVID-19
bilateral pneumonia.
Results. Cotton wool exudates were evident in six out
of 27 patients evaluated, a 22%. Cotton wool
exudates are a marker vascular disease severity
in other medical context, that is diabetes and
hypertension, and are associated with increased
risk for acute vascular events. Whether antiaggre-
gation therapy may play a role on fundoscopic-
selected patients with COVID-19 requires prospec-
tive trials.
Keywords: COVID-19 retinopathy, COVID-19 retinal
microangiopathy, COVID-19 vascular risk.

in the pathogenesis of systemic vascular diseases

Introduction
In December 2019, an outbreak of a novel coron-
avirus-associated disease (COVID-19) was first
reported in Wuhan, China, and has then subse-
quently affected numerous countries worldwide.
According to recent reports of the World Health
Organization (WHO), United States has become the
country with highest number of confirmed cases,
followed by Spain and Italy. COVID-19 is caused by
SARS-CoV-2, a betacoronavirus that uses the angio-
tensin-converting enzyme-related carboxypeptidase
(ACE2) receptor to gain entry into cells [1]. ACE2
receptor is widely expressed in multiple organs,
including the retina, an extension of the central
nervous system [2, 3]. The ACE2 receptor is involved
that produce ocular manifestations, such as diabetic
and hypertensive retinopathy. Fundoscopic retinal
examination is essential for evaluation of vascular
systemic damage in diabetes and hypertension.
On the other hand, coronaviruses cause ocular infec-
tions in animals. Clinical entities such as conjunctivi-
tis, anterior uveitis, retinitis and optic neuritis have
been documented in feline and murine models [4].
Thrombotic events including ischaemic brain dam-
age are a major complication of COVID-19. There-
fore, retinal examination may discover an up to
now unrecognized retinal damage in COVID-19
patients.

ª 2020 The Association for the Publication of the Journal of Internal Medicine 1
 COVID19 retinal microangiopathy / M. F. Landecho et al.

Table 1. Main clinical and biochemical characteristics of patients with cotton wool spots (CWS present) and patients without
cotton wool spots (CWS absent). Days delay: Refers to the number of days between COVID-19 diagnosis and fundoscopic
evaluation

CWS present N:6 CWS absent N: 21

Median age, years (range) 56 (35) 61 (41)
Gender (% males) 66% 66%
Hypertension, n (%) 3 (50%) 9 (43%)
Diabetes, n (%) 1 (17%) 5 (24%)
Obesity, n (%) 1 (17%) 6 (28%)
Days delay, median (range) 45 (30-57) 44 (30-58)
1
D-dimer (mg dL )
On admission, median (range) 730 (270-2370) 940 (340-6540)
Highest value, median (range) 1135 (380-4260) 1590 (360-11980)
On funduscopic day, median (range) 385 (270-4260) 400 (280-9770)
1
Lymphocyte count (10E9 L )
On admission, median (range) 1.53 (0.7-2.26) 1.12 (0.57-2.71)
Lowest value, median (range) 1.12 (0.6-2.12) 0.95 (0.63-2.42)
On funduscopic day, median (range) 2.14 (0.97-2.44) 1.49 (0.93-4.11)
1
CRP (mg dL )
On admission, median (range) 7.96 (0.2-15.73) 5.72 (0.86-34.03)
Highest value, median (range) 10.24 (0.2-15.73) 11.07 (1.17-34.03)
On funduscopic day, median (range) 0.57 (0.3-10.4) 0.24 (0.03-1,47)

and the fundoscopic evaluation. Table 1 shows

Methods
We have evaluated 27 asymptomatic subjects with
previous COVID-19 respiratory tract infection,
fourteen days after hospital discharge, with retinal
fundoscopic, optical coherence tomography (OCT)
and OCT angiography. Only patients with a nega-
tive SARS-CoV-2 pharyngeal swab and positive
antibodies were evaluated.
Results
Twenty-six patients had developed bilateral pneu-
monia, with the characteristic bilateral multifocal
ground-glass opacities, one of them requiring
mechanical ventilation. One patient did not
develop pulmonary infiltrates in the CT scan. Five
patients had unilateral elliptical cotton wool spots
(CWS) and one case bilateral, including the
patient who did not develop pneumonia. In the
case who required orotracheal intubation, there
were no CWS at the moment of fundoscopic
examination, 58 days after diagnosis. All patients
received daily prophylactic dose of low molecular
weight heparin between the COVID-19 diagnosis
the main characteristics of the population. No
relevant clinical or biochemical differences could
be found.
Five patients had unilateral CWS and one case
bilateral. Figure 1 shows the retinal fundus explo-
ration and the B-scan optical coherence tomogra-
phy of patient 1. Figure 2 shows the retinal fundus
exploration and the B-scan optical coherence
tomography of patient 3.
Discussion
The main finding of our series is a 22% of retinal
microangiopathy manifested as CWS at a mean of
43 days after COVID-19 first symptom. There were
no signs of vitreoretinal inflammation such as
vasculitis, haemorrhages, chorioretinal infiltrates
or vitritis, as they appear in other viral retinitis.
Our report confirms the findings in patients with
respiratory presentation of one previous document
that has reported similar retinal disease in 4
subjects with neurologic symptoms [5] performed
in a similar range of days. CWS are self-limited in a

2 ª 2020 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine
 COVID19 retinal microangiopathy / M. F. Landecho et al.

Fig. 1 45 years old woman showing bilateral cotton wool spots (arrows) in retinal fundus exploration. B-scan optical
coherence tomography shows swelling of the retinal nerve fibre layer (asterisks).

Fig. 2 69 years old man showing cotton wool spot (CWS) in his right eye (arrow) in retinal fundus exploration. B-scan
optical coherence tomography shows swelling of the retinal nerve fibre layer (asterisk). Optical coherence tomography
angiography shows the absence of a signal at the CWS location (arrow heads).

ª 2020 The Association for the Publication of the Journal of Internal Medicine 3
Journal of Internal Medicine
 COVID19 retinal microangiopathy / M. F. Landecho et al.
few weeks, and we cannot exclude that their
incidence could have been higher if retina had
been explored earlier during the active phase of the
disease, but CWS do not seem to affect all patients
with COVID-19.
CWS comprise localized accumulations of axoplas-
mic debris within adjacent bundles of unmyelinated
ganglion cell axons and are sentinels of retinal nerve
fibre layer vascular pathology. Asymptomatic ocular
microangiopathic syndrome is highly prevalent in
other vascular systemic diseases (i.e. diabetes and
hypertension) and after viral infections, as the
human immunodeficiency virus (HIV) disease [6,
7]. In diabetic patients, CWS are caused by ischae-
mia after occlusion of a feeder arteriole, whilst the
pathogenesis of the HIV CWS is still a matter for
conjecture, but a direct viral effect seems to play a
significant role [7]. It is noteworthy that different
morphologies of the CWS have been reported, being
HIV-associated CWS significantly more eccentric
[7]. This difference suggests that, at some level, the
pathogenesis of these two types of CWS may be
different. The SARS-CoV-2, as the diabetic CWS, is
elliptical. Whether COVID-19 retinal microangiopa-
thy is a direct viral effect or shares the diabetic
mechanism of damage requires further investiga-
tion. It is remarkable that ACE2 is the primary
enzyme of the vasoprotective axis of the renin–
angiotensin system, and diabetic retinopathy is
associated with impaired balance of retinal renin–
angiotensin–aldosterone axis. ACE2 downregula-
tion might play a major role in inducing the devel-
opment of retinal ischaemia [2, 3, 6] and even act as a
marker of endothelial disease [2]. It is noteworthy
that SARS-CoV and likely SARS-CoV-2 lead to
downregulation of the ACE2 receptor [1]. Beyond
this mechanism, CWS might serve as an in vivo
marker of risk for acute vascular events, as in the
diabetic and hypertensive vascular disease [8].
There are at least two major possible ways of
vascular damage in COVID-19 patients: first, an
hypercoagulable state, disseminated intravascular
coagulation (DIC)-like [9], and second a vasculitis-
like process, due to direct viral infection of the
endothelial cell and diffuse endothelial inflamma-
tion [10]. According to the DIC standard of care, all
our patients received prophylactic low molecular
weight heparin but despite this, at least a 22% of the
patients have developed CWS. COVID-19-related
vascular disease is a major concern in the clinical
practice. Not in vain, some studies have revealed
that 71.4% of nonsurvivors of COVID-19 matched
4 ª 2020 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine
the grade of overt DIC and showed abnormal coag-
ulation results during later stages of the disease [9].
There is also an increased incidence of acute neu-
rovascular events [11], and even COVID-19 post-
mortem biopsy studies have also reported
pulmonary arterial thrombosis [12–15]. The finding
of thrombi in medium size pulmonary vessels raises
the question of the potential benefits of treating
COVID-19 patients with antiaggregation, added to
low-dose heparin. Based on these observations, we
hypothesize that fundoscopic evaluation might help
to identify patients with signs of arterial microan-
giopathy in whom antiaggregation could play an
important therapeutic role.
In conclusion, the occurrence of CWS is a relevant
ocular manifestation of COVID-19, and fundo-
scopic examination might help to identify subjects
with endothelial disease that are prone to acute
vascular events. Therefore, we believe that a fun-
doscopic examination of COVID-19 patients at
admission should be indicated. Whether these
patients benefit from antiaggregation therapy
requires further investigation.
Acknowledgements
We want to thank all the relatives of the patients in

our series, Aurora Alvarez, the COVID-19 medical
team of the Clinica Universidad de Navarra, and
the auxiliary and cleaning staff of the hospital. The
ethics committee of the Clinica Universidad de
Navarra has evaluated and found no concerns in
the study.
Conflict of interests
None to declare.
Funding source
None.
Author contribution
Manuel Fortu  n Landecho: Conceptualization
(lead); Writing-review & editing (lead). Alfredo
Garcıa-Layana: Conceptualization (equal); Writ-
ing-review & editing (equal).
Key points
To the best of our knowledge, this is the first paper
to confirm a high prevalence of COVID-19 retinal
 COVID19 retinal microangiopathy / M. F. Landecho et al.
microangiopathy in patients with respiratory
symptoms.
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Correspondence: Manuel Fort un Landecho, MD, Internal Medi-
cine Department, Covid19 Department, Clinica Universidad de
Navarra, Avenida Pio XII, No 36, 31008 Pamplona, Navarra,
Spain.
(e-mail: mflandecho@unav.es)
Alfredo Garcıa Layana, Ophtalmology Department, Clinica
Universidad de Navarra, Avenida Pio XII, No 36, 31008 Pamplona,
Navarra, Spain.
(e-mail: aglayana@unav.es)
ª 2020 The Association for the Publication of the Journal of Internal Medicine 5
Journal of Internal Medicine