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RADIATION RESEARCH 195, 1–24 (2021)
0033-7587/21 $15.00
Ó2021 by Radiation Research Society.
All rights of reproduction in any form reserved.
DOI: 10.1667/RADE-20-00188.1
REVIEW
Commonalities Between COVID-19 and Radiation Injury
Carmen I. Rios,
1
David R. Cassatt, Brynn A. Hollingsworth, Merriline M. Satyamitra, Yeabsera S. Tadesse,
Lanyn P. Taliaferro, Thomas A. Winters and Andrea L. DiCarlo
Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy
and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, Maryland
Rios, C. I., Cassatt, D. R., Hollingsworth, B. A., Satyamitra,
M. M., Tadesse, Y. S., Taliaferro, L. P., Winters, T. A. and
DiCarlo, A. L. Commonalities Between COVID-19 and
Radiation Injury. Radiat. Res. 195, 1–24 (2021).
As the multi-systemic components of COVID-19 emerge,
parallel etiologies can be drawn between SARS-CoV-2
infection and radiation injuries. While some SARS-CoV-2-
infected individuals present as asymptomatic, others exhibit
mild symptoms that may include fever, cough, chills, and
unusual symptoms like loss of taste and smell and reddening
in the extremities (e.g., ‘‘COVID toes,’’ suggestive of
microvessel damage). Still others alarm healthcare provid-
ers with extreme and rapid onset of high-risk indicators of
mortality that include acute respiratory distress syndrome
(ARDS), multi-organ hypercoagulation, hypoxia and car-
diovascular damage. Researchers are quickly refocusing
their science to address this enigmatic virus that seems to
unveil itself in new ways without discrimination. As
investigators begin to identify early markers of disease,
identification of common threads with other pathologies
may provide some clues. Interestingly, years of research in
the field of radiation biology documents the complex multi-
organ nature of another disease state that occurs after
exposure to high doses of radiation: the acute radiation
syndrome (ARS). Inflammation is a key common player in
COVID-19 and ARS, and drives the multi-system damage
that dramatically alters biological homeostasis. Both condi-
tions initiate a cytokine storm, with similar pro-inflamma-
tory molecules increased and other anti-inflammatory
molecules decreased. These changes manifest in a variety
of ways, with a demonstrably higher health impact in
patients having underlying medical conditions. The poten-
tially dramatic human impact of ARS has guided the science
that has identified many biomarkers of radiation exposure,
established medical management strategies for ARS, and led
to the development of medical countermeasures for use in
the event of a radiation public health emergency. These
efforts can now be leveraged to help elucidate mechanisms
of action of COVID-19 injuries. Furthermore, this intersec-
tion between COVID-19 and ARS may point to approaches
that could accelerate the discovery of treatments for
both. Ó2021 by Radiation Research Society
INTRODUCTION
The world is currently in the grip of a global pandemic.
As of September 10, 2020, over 50 million cases of
COVID-19, the disease caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), have been report-
ed worldwide. At the forefront of directing research
activities focused on combating COVID-19 is the National
Institute of Allergy and Infectious Diseases (NIAID) within
the U.S. National Institutes of Health (NIH). In April 2020,
the NIAID published the NIAID Strategic Plan for COVID-
19 Research
2
describing NIAID’s efforts to better under-
stand SARS-CoV-2 and to accelerate the development of
safe biomedical tools. The plan is a well-defined document
that focuses on four research priorities: improving funda-
mental knowledge of SARS-CoV-2 and COVID-19;
supporting the development of diagnostics and assays;
characterizing and testing therapeutics; and developing safe
and effective vaccines against SARS-CoV-2. A detailed
research plan for each priority area is described in the
document.
The novelty of the 2019 novel coronavirus disease
(COVID-19) is underscored by the fact that there are no
FDA-approved or licensed therapeutics specific for corona-
viruses. The traditional drug development pathway for
therapeutics (and diagnostic tools) can be a years-long
process with milestones that require extensive resources to
achieve. However, the urgency of the COVID-19 pandemic
emphasizes the need for rapid development and testing of
promising therapeutic and diagnostic candidates. Approach-
es to accelerate the development process are being explored
in other areas of science where overlapping trends can be
1
Address for correspondence: RNCP, DAIT, NIAID, NIH, 5601
Fishers Lane, Room 7A69, Rockville, MD 20892-9828 (20852 for
express mail); email: carmen.rios@nih.gov.
2
NIAID strategic plan for COVID-19 research FY2020–FY2024,
April 22, 2020. (https://bit.ly/3mFnb2e)
1
investigated. Therapeutics developed for other clinical
indications could potentially be repurposed to treat
COVID-19; some of those possibilities are discussed in
this review. Likewise, pathological features and manner of
progression of other indications similar to COVID-19 could
elucidate how to effectively mitigate and treat this disease.
In this review, we describe observed parallels between
COVID-19 and the biological effects of radiation injury that
include immediate and long-term components: the acute
radiation syndrome (ARS) and the delayed effects of acute
radiation exposure (DEARE).
The Radiation and Nuclear Countermeasure Program
(RNCP) within the NIAID is one such program in which the
scientific work is relevant to the COVID-19 response. The
RNCP was initiated in 2004, with the mission of supporting
research to develop medical countermeasures to diagnose
(biodosimetry) and treat radiation injuries leading to ARS
and DEARE in the wake of a radiation public health
emergency. The marked similarities between COVID-19
and radiation injuries described in this review have a major
underpinning: the inflammatory response. Several products
currently in development within the RNCP to treat radiation
exposure operate by targeting inflammation that can lead to
tissue damage. In fact, approaches developed to treat
radiation-induced lung fibrosis and vascular damage merit
investigating and are discussed here in the context of
COVID-19.
TARGETS
Here we highlight some of the systems and immunolog-
ical areas affected by both COVID-19 and acute radiation
exposure, albeit to different levels. In both cases, the result
is a systemic insult that can cause damage to many parts of
the body, including the vascular system, lung, heart,
kidneys, liver, gut, eyes and brain. Regardless of the target
organ, the hyperactivation of the immunogenic pathways
are at the heart of the body’s response to overcome SARS-
CoV-2 and acute radiation exposure (1). Cytokines are
produced by a variety of immune cells (i.e., macrophages, B
lymphocytes, T lymphocytes and mast) and non-immune
cells (i.e., endothelial, fibroblasts and stromal). Under
normal circumstances, cytokines have a short half-life and
act as local mediators within a microenvironment; therefore,
circulating cytokines in the blood are below the limit of
detection of most commercially available assay kits (2).
This complex communication network provides a healthy
immune system with the proper signals to mount a
proportionate response against an infectious agent or
inflammatory stimuli. In other cases, the reaction is so
strong that circulating cytokine levels surge, resulting in a
‘‘cytokine storm’’ (also called hypercytokinemia
3
)oran
overaction of the immune system creating a generalized
inflammatory response that can lead to systemic tissue
damage. The cytokine storm is the nexus between SARS-
CoV-2 infection and radiation exposure; both result in
systemic inflammation that ravages the body (1, 3).
A wealth of early literature has described the cytokine
storm syndrome (CSS) in COVID-19 patients (4–15). For
example, in a study of 50 patients, expression levels of 14 of
48 cytokines studied were associated with disease severity
and progression, with interferon (IFN)-c-induced protein 10
and monocyte chemotactic protein-3 noted as excellent
predictors of disease progression (16). Increases in
granulocyte-macrophage colony-stimulating factor (GM-
CSF) and interleukin-6 (IL-6) due to T-cell overactivation
were also noted (17). Another retrospective study with
3,939 patients shows both mild and severe forms of
COVID-19 disease resulting in changes in circulating
leukocyte subsets and cytokine secretion (8). In particular,
Vaninov et al. noted that persistent high levels of three
cytokines (CXCL10, CCL7 and IL-1 receptor antagonist)
were associated with increased viral load, loss of lung
function, lung injury and a fatal outcome (12). Based on
these kinds of findings of elevated levels of specific
cytokines, in June 2020 the FDA issued an Emergency
Use Authorization (EUA) for an in vitro diagnostic test
based on measuring the circulating IL-6 levels in serum or
plasma for the management of patients with COVID-19
4
(discussed in more detail below). However, emerging
technologies measuring ‘‘cytokine signatures’’ demonstrate
variability across subjects and highlight the need for the
development of personalized treatments based on these data.
As observed with COVID-19, cytokines are also released
by many cells after radiation exposure, including endothe-
lial cells, fibroblasts, immune cells and parenchymal cells.
The interplay and early activation of inflammatory reactions
involving proteins in cytokine cascade, such as fibroblast
growth factor (FGF), transforming growth factor (TGF),
tumor necrosis factor (TNF-a), and interleukins (ILs) is
thought to be responsible for DEARE. Cytokines and
chemokines that attract immune cells and lead to inflam-
mation include IL-1aand IL-6. Inflammatory cells cause
numerous other changes to occur, such as cell death,
promotion of fibrosis and swelling of the tissue. These
cytokines are involved in both early and late reactions, like
the major cytokines in the response of skin cells to ionizing
radiation, and include IL-1, IL-6, tumor necrosis factor
(TNF)-a, transforming growth factor (TGF)-b, which can be
pro-or anti-inflammatory depending on the tissue and
context of release, and the chemokines IL-8 and eotaxin
(18). Cytokines can be broadly grouped as pro-inflamma-
tory cytokines such as TNF-a,IL-1aand b,IL-17;
angiogenic/vascular endothelial growth factor (VEGF),
3
NIH/National Cancer Institute. NCI Dictionaries. Cytokine
storm. (https://bit.ly/35RIp73)
4
U.S. Food and Drug Administration. Letter to Linda McCam-
mack, Senior Regulations Manager, Roche Diagnostics. Emergency
use authorization for Elecsys IL-6. June 2, 2020. (https://bit.ly/
32NzWzG)
2RIOS ET AL.
TNF-aand FGF; anti-inflammatory IL-4, IL-10 and TGF-b;
pro-fibrotic IL-6 and TGF-b; immune IL-2, IL-4 and IL-7;
and hematopoietic CSF1, GM-CSF, IL-3 and EPO (19).
Interestingly, persistence of inflammatory cytokines, che-
mokines and growth factors, such as TGF-b, IFN-c, ET-1,
IL-4, IL-13, lead to pulmonary fibrosis (20). Notably, IL-6,
which appears to be a key player in the response to SARS-
CoV-2, is altered after irradiation as well; however, its role
in radiation-induced lung injury is still unclear (21).
In addition to the cytokine storm, dysregulation of the
renin-angiotensin system (RAS) plays a critical role in the
pathogenesis of COVID-19 (22) and radiation exposure.
The RAS pathway, which regulates the body’s fluid
regulation system, is dependent on angiotensin converting
enzyme (ACE) and ACE2. ACE regulates blood pressure,
water, and sodium levels as well as inflammation,
proliferation and vasoconstriction. ACE2, the target recep-
tor of SARS-CoV-2, is involved in degrading AngII to
produce Ang 1-7 and then further to angiotensin 1-5, which
is the effector peptide (23). ACE2 can be found in a variety
of organs (e.g., heart, kidney, adipose tissue, vascular
smooth muscle cells, brain tissue, testis, gastrointestinal
(GI) tract, etc.). Together ACE/ACE2 promote vasodilation
to reduce blood pressure and maintain homeostasis of the
RAS. ACE2 is expressed throughout the body, so it is no
surprise that it plays many physiological roles, which extend
beyond its ability to reduce blood pressure. These include
cardiac and lung protection by ACE2. A mouse study by
Imai et al. shows that AngII, upregulated by ACE, drives
severe lung failure through the AT1a receptor while ACE2
and the AT2 receptors protect against lung injury. The
group showed that exogenous recombinant human ACE2
reduces acute lung failure in ACE2 knockout and wild-type
mice (24, 25), and impacts GI dysregulation and diabetic
complications (26). As SARS-CoV-2 (27) binds ACE2, it is
possible that ACE2 receptors are downregulated, causing an
imbalance in the RAS (28).
Both cytokine and RAS disequilibria may have implica-
tions in the development of lung and other organ injuries for
both COVID-19 (3, 22, 27) and ionizing radiation exposure
(29, 30), although the interplay is complex and not
completely understood. In general, SARS-CoV-2 infection
(31) and ionizing radiation exposure (31) trigger pro-
inflammatory cytokines (e.g., IFN-a, IFN-c, IL-1b, IL-6,
IL-12, IL-18, IL-33, TNF-a, TGF-b, etc.). In the case of
COVID-19, the lung is the most prevalent initial target and,
in some cases, the injury progresses from pneumonitis (32,
33) to acute respiratory distress syndrome (ARDS). This
heightened chronic inflammatory response creates a pro-
fibrotic environment that yields long-term fibrosis followed
by organ dysfunction. Similarly, exposure to radiation can
also result in lung fibrosis (34–36) as well as injury to other
organs (37–39).
The vasculature is also targeted by SARS-CoV-2, as
evidenced by the prevalence of systemic thrombotic events
(40), endotheliitis (endothelial inflammation) (41)and
‘‘COVID toes’’ (suggesting dysfunction of microvessels
in the extremities) (42, 43). The virus has been shown to
directly infect endothelial cells (41), and their subsequent
dysregulation likely explains the many vascular coagulop-
athies and thromboses that have been noted in COVID-19
patients. Recently, Zamboni (44) described COVID-19 as a
vascular disease, with the endothelial cell emerging as a
potent target for SARS-CoV-2, while the endothelium is
called ‘‘the lynchpin’’ of COVID-19 pathogenesis, orches-
trating the cytokine storm and damage to multiple organs
(45). In severe cases, this dysfunction has led to strokes (46)
and other cardiovascular involvement (47). Similarly, acute
radiation exposure leads to vascular injury (48) by way of
apoptosis and senescence of endothelial cells as well as via
an increase in cell adhesion molecules (49) and dysregu-
lation of coagulation homeostasis (50).
Another common target of SARS-CoV-2 and acute
radiation exposure is the pyroptosis pathway or caspase-1-
dependent programmed cell death of eukaryotic cells.
Pyroptosis is a mechanism by which the body’s innate
immune system clears pathogens and promotes an adaptive
immune response. Caspase-1 initiates inflammation that
results in the formation of plasma-membrane pores in
pathogen-infected cells, enabling water to enter, causing
swelling and osmotic lysis. In addition, caspase-1 promotes
cleavage of chromosomal DNA and nuclear condensation.
Caspase-1 is activated by Toll-like receptors (TLRs) and
NOD-like receptors (NLRs) present on immune cells, such
as macrophages or epithelial cells, which sense extracellular
and intracellular danger signals produced by pathogens or
tissue injury. This cellular communication network results
in an inflammatory cascade initiated by NF-jB, mitogen-
activated protein kinase (MAPK)- and interferon-regulatory
factor (IRF)- dependent pathways, activating IFN-a/b,
TNF-a/b, IL-12, IL-6, IL-8 and pro-IL-1b. The pyroptosis
pathway is also implicated in immune cell death (e.g., in the
spleen) after acute radiation exposure (51, 52). Furthermore,
the NF-jB/TNF-asignaling pathway is also activated in
response to ionizing radiation, resulting in a similar
cytokine cascade. In fact, a recently published study
showed that pyroptosis may play a role in radiation-induced
lung inflammation and fibrosis (53).
BIOMARKERS
Biomarkers in Pathophysiology of COVID-19 and Radiation
Injury
There is a remarkable similarity in the pattern of biomarker
response to SARS-CoV-2 infection and radiation exposure.
Significant changes in hematological, chemical, inflammato-
ry and immune biomarkers are seen in COVID-19 and in
irradiated patients. Although the insult (infection or acute
radiation exposure) is vastly different, the ensuing patholo-
gies converge to multiorgan dysfunction (MOD), resulting in
multiorgan failure (MOF) and mortality. Biomarkers unique
REVIEW 3
to each insult, such as smell dysfunction for COVID-19, or
cytogenetic, genomic or metabolomic approaches for radia-
tion biodosimetry are not discussed here.
Hematology
The classical approach of hematology has emerged as a
valuable tool in predicting outcome as well as stratifying
and management of COVID-19 patients (54–59). For
example, a retrospective analysis compared hemocyte
counts (neutrophils, lymphocytes and platelets; or ‘‘NLP
score’’) and found a strong correlation between NLP score
and COVID-19 disease progression, while another pub-
lished study noted lymphocyte decrease associated with
COVID-19 severity (60, 61). Furthermore, Chen et al.
conducted a retrospective study on 548 patients and noted
that the counts of lymphocytes, T-cell subsets, eosinophils
and platelets decreased markedly, especially in severe/
critical and fatal patients. Increased neutrophil count and
neutrophil-to-lymphocyte ratio were predominant in severe/
critical cases or non-survivors (61). From separate studies, it
was observed that an increase in the neutrophil-to-
lymphocyte ratio (NLR) is an early warning signal for
severe COVID-19 (59, 62, 63). These data are further
supported by findings from a published study of 75 patients
from Suzhuo, China with confirmed COVID-19 infection;
common COVID-19 abnormal hematological indexes on
admission included hyperfibrinogenemia, lymphopenia,
elevation of D-dimer, and leukopenia, which were signif-
icantly different between the mild/moderate and severe
COVID-19 groups. Furthermore, the dynamic change of
NLR and D-dimer level can distinguish severe COVID-19
cases from the mild/moderate (64).
Hematological data could be further refined to interrogate
a single cell population (such as lymphocytes or platelets)
that yielded significant correlation with COVID-19 pro-
gression and severity. A meta-analysis of 3,099 patients
from 24 different studies showed that patients who did not
fare well had low lymphocyte counts (mean difference of –
361.06/ll) compared to patients who had good outcomes
(65). Other researchers have also reported lymphopenia as a
key biomarker in COVID-19 patients (66–68); Terpos et al.
(68) referred to lymphopenia as ‘‘a cardinal laboratory
finding, with prognostic potential,’’ urging for the need for
longitudinal evaluation of parameters to follow the
dynamics of the disease progression. Thrombocytopenia is
also commonly noted among patients hospitalized with
COVID-19 and a low platelet count is associated with
higher mortality (57, 69–74). It is hypothesized that SARS-
CoV-2 infects both bone marrow cells and platelets via the
CD13 receptor, inducing growth inhibition and apoptosis.
This entry disrupts hematopoiesis, resulting in thrombocy-
topenia. Another cause of thrombocytopenia is attributed to
lung injury due to activation, aggregation, and retention of
platelets in the lung. The formation of thrombus at the site
of lung injury leads to decreased platelet production and
increased consumption (75, 76). Interestingly, in most cases
the platelet decreases did not reach a level where
spontaneous bleeding occurred.
As seen with COVID-19 patients, radiation exposure also
results in profound hematological perturbations in humans
as well as irradiated animal models, characterized by
granulocytopenia, lymphopenia and thrombocytopenia
(77–81). Unlike COVID-19, significant decreases in
neutrophils, in addition to other cytopenias, is a hallmark
of ARS (82). The SEARCH (System for Evaluation and
Archiving of Radiation accidents based on Case Histories)
(82) database contains 824 clinical cases from 81 radiation
accidents in 19 countries and allows detailed analysis of the
time course of ARS, with the intention to study all medical
aspects of ARS and to derive medical treatment protocols
for radiation accident victims (MEdical TREatment Proto-
cOLs; METREPOL) (83). The hematopoietic syndrome can
be characterized by granulocyte count kinetics (84). The
Radiation Emergency Medical Management (REMM)
5
website provides guidance on triaging radiation accident
victims based on lymphocyte depletion kinetics. The
kinetics of lymphocyte depletion have been shown to be
directly related to the absorbed radiation dose from 0.5 to 10
Gy (85–87). Furthermore, the ratio of neutrophil to
lymphocyte has been employed to determine the radiation
dose exposure (88–90). Interestingly, platelet depletion
alone has not been used to determine radiation dose,
although thrombocytopenia correlates directly with radia-
tion dose and platelet utilization at sites of active bleeding.
Serum Biomarkers
Patients with moderate and severe COVID-19 showed
significant increase in levels of serum amyloid A (SSA), C-
reactive protein (CRP) which positively correlated to
COVID-19 pneumonia (24), and serum albumin (ALB)
levels (P,0.05) (62). Radiation also induces increases in
the serum and urine proteome. CRP and serum amylase are
commonly elevated after radiation exposure (91–93). In the
criticality accident at Tokaimura, all three patients presented
with elevated serum amylase (94). CRP levels were reported
to correlate with clinical outcome in patients exposed to
radiation during the Chernobyl nuclear accident (95). From
a published study that identified 260 radiation-responsive
proteins (96), Partridge et al.(97) narrowed the panel to IL-
6, IL-1b, TNF-aand TGF-blevels as being strongly
correlated to irradiation, with IL-6 emerging as the best
marker for COVID-19 and acute radiation exposure.
Electrolytes
Electrolyte imbalance with reduced potassium, calcium,
chloride and sodium is observed in patients with COVID-19
5
U.S. Dept. of Health and Human Services. REMM/Radiation
Emergency Medical Management. Guidance on diagnosis and
treatment for healthcare providers. (https://www.remm.nlm.gov/)
4RIOS ET AL.
(72, 76, 98). Pooled analysis of data on serum electrolytes
confirms that hyponatremia, hypokalemia and hypocalce-
mia are associated with COVID-19 severity; however, the
authors cautioned that additional information such as
calcium concentrations, serum albumin levels and the
patients’ fluid status is necessary for accurate interpretation
of laboratory findings (99). Interestingly, the authors draw a
correlation between electrolyte imbalance and progression
of COVID-19 disease and MOF. SARS-CoV-2 binds to its
host receptor, ACE2, and reduces ACE2 expression, leading
to increased angiotensin II, which can cause increased
potassium excretion by the kidneys resulting in hypokale-
mia, while plasma angiotensin II is purported to be a
mediator of ARDS and ensuing MOF seen in a significant
number of COVID-19 patients (100). Another cause of
electrolyte loss in COVID-19 patients is attributed to GI
causes such as diarrhea and emesis (101). The U.S. Centers
for Disease Control (CDC) has described a similar
electrolyte imbalance, accompanied by diarrhea and emesis,
due to damage and disruption of the intestine after radiation
exposure (102, 103).
Immune Biomarkers
Lymphocyte counts provide a rapid snapshot of the
prognosis for patients with COVID-19. Delving into the
lymphocyte subsets provides a clearer understanding of the
patient’s immune status, with both diagnostic and prognos-
tic value (104). In a 103-patient study, a significant decrease
in T-cell populations were reported. In particular, the CD3
þ
,
CD4
þ
, CD8
þ
and NK cell counts dropped, with the CD4
þ
/
CD8
þ
ratio increased in COVID-19 patients compared to
healthy controls (105). In other published studies, a
correlation was noted between the severity of disease and
reduction in T-cell subunits (61, 66) as well as decreases in
B-cell numbers (106).
Persistent changes in the immune system after radiation
exposure are manifested as abnormalities in the lymphoid
populations and function (107). Radiation studies have
documented immediate changes in T-cell subsets (108) and
Bcells(109) linked to radiation dose. In particular,
depletion of CD8
þ
cells has been correlated with absorbed
radiation at low doses (110). In atomic bomb (A-bomb)
survivors, a decrease in CD4 helper T-cell populations,
attenuated T-cell function, as well as an increase in B-cell
populations, which could drive long-term inflammation.
Radiation dose-dependent reduction in CD4
þ
cell popula-
tion has also been reported (111, 112). While these metrics
are not used to monitor disease progression, they are
indications of the continued immune dysfunction observed
in patients after radiation exposure (113).
Vascular Dysfunction
Histological analysis of COVID-19 has shown that the
presence of SARS-CoV-2 within endothelial cells was
associated with clusters of inflammatory cells, suggesting
that infection initiates endotheliitis throughout the entire
human body, leading to systemic macro and microcircula-
tory dysfunction in vascular beds (44). VEGF-D was noted
as an indirect procoagulant biomarker of COVID-19
progression (114) and angiopoietin-2 (a marker for
endothelial activation), was associated with microvascular
dysfunction (115). Vascular abnormalities such as vascular
thickening, detected by thoracic computed tomography
(CT), was reported to be significantly associated with
COVID-19, when compared to non–COVID-19 pneumonia
(59% versus 22%, P,0.001) (116). Ultimately, endotheli-
opathy converges with COVID-19-associated coagulopa-
thies; a recently published study showed significant
elevation in markers of endothelial cell and platelet
activation with mortality strongly correlated to von
Willebrand factor (VWF) antigen and plasma thrombomo-
dulin (117).
Vascular dysfunction resulting from radiation exposure
has also been reported. Of the 28 people who died within 98
days of the Chernobyl criticality incident, deaths were
attributed to skin, GI and lung reactions, but most deaths
were characterized by circulatory problems, with a high
incidence of edema and focal hemorrhages (118). After the
Tokaimura Nuclear Plant accident in Tokai, Japan, Akashi
discussed the possible role of inflammation and hemorrhage
in radiation-induced MOF. In a review of 110 cases
histories of radiation accidents spanning 1945 through
2000, the authors analyzed MOF after total-body irradiation
(TBI) and stated that ‘‘. . .symptomatology of organ system
involvement could be traced not only to the pathophysiol-
ogy of the rapidly turning over cell renewal systems but – of
equal or more importance – to the vascular system and
specifically, to the endothelial components.’’ (119). The
primary target of radiation injury to the vasculature is the
endothelial cell. The acute phase of damage occurs within
hours to weeks postirradiation, and is characterized by
endothelial swelling, vascular permeability and edema,
lymphocyte adhesion and infiltration, and apoptosis (52).
Radiation-induced vascular biomarkers include inflamma-
tory signals, endothelial activation and adhesion markers,
and prothrombic markers (48, 120, 121), similar to those
reported for COVID-19.
As of September 10, 2020, the FDA has authorized EUAs
for more than 150 individual molecular diagnostic tests for
SARS-CoV-2. As a sampling, from February 4, 2020 to
June 18, 2020, a total of 85 tests received EUA
authorization, which included 37 tests for detection of
nucleic acids from SARS-CoV-2 and one antigen diagnostic
test, with required conditions for manufacturers and
authorized laboratories.
6
Similarly, as of mid-June 2020,
the FDA had authorized more than 20 serology biomarker
tests, with the caveat to ‘‘always refer to the complete
instructions for use to put these estimates into the proper
6
U.S. Food and Drug Administration. In vitro diagnostics EUAs.
(https://bit.ly/3mEFODt)
REVIEW 5
context and to understand how to use and interpret these
tests.’’ On June 2, 2020, the FDA authorized the only in
vitro diagnostic test for the management of patients with
COVID-19, which is based on measuring the circulating IL-
6 levels in these patients. In stark contrast, no radiation
biodosimetry test has been cleared/authorized by the FDA.
PATHOLOGY
As more information becomes available, it is increasingly
apparent that COVID-19 is not just a pulmonary affliction,
but a multi-organ disease. Curiously, many symptoms as
well as underlying pathogenesis in this multi-organ injury
caused by SARS-CoV-2 are similar to the multi-organ
injury caused by acute ionizing radiation exposure. In a
nuclear incident, a person’s entire body may be exposed to
large doses of damaging ionizing radiation, while SARS-
CoV-2 can only infect cells co-expressing angiotensin-
converting enzyme 2 and transmembrane serine protease 2
(TMPRSS2). The presence of these proteins on a wide
variety of cell types throughout the body such as airway
epithelial cells, alveolar epithelial cells, lung macrophages
and vascular endothelial cells (122, 123), absorptive
enterocytes of the ileum and colon (124), explains the
widespread damage caused by the infection (124). Indeed,
SARS-CoV-2 RNA has been detected in sputum, nasal
swabs, saliva, feces, blood, tears, urine and cerebrospinal
fluid (125–128). Despite the differences in the initial cause
of injury, systemic inflammation and coagulopathy, includ-
ing disseminated intravascular coagulation (DIC) are
hallmarks of both COVID-19 (123, 129–131) and acute
radiation injury, with pyroptosis (51, 53, 131, 132) and
neutrophil extracellular traps (133, 134) found in both. As
noted in COVID-19 patients, hematopoietic ARS patients
develop lymphopenia, thrombocytopenia and neutropenia
due to bone marrow damage (135), possibly further
contributing to multi-organ damage and failure. These
disease processes found in both COVID-19 and acute and
delayed radiation syndromes may directly cause or further
exacerbate injury and pathogenesis in multiple organ
systems (Fig. 1). In fact, multi-system inflammatory
syndrome in children with COVID-19 has recently been
described and affects a wide range of organs and systems
(136).
Pulmonary disease and symptoms are the most common
presentation of COVID-19 and respiratory failure is the
most common cause of death in those with COVID-19
disease (98, 137), whereas lung damage in irradiated
FIG. 1. Panel A: Schematic showing the human organ systems affected by radiation exposure and comprise
both acute and delayed radiation syndromes (Published and modified with permission; licensed from ClipArt
ETC: https://bit.ly/3mHcyvG). Panel B: A representative list of extrapulmonary symptoms observed in COVID-
19 (SARS-CoV-2 infection) (353). Coronavirus image published and modified, with permission, from the
University of Virginia School of Medicine (https://at.virginia.edu/32MutJv).
6RIOS ET AL.
patients is a later effect (compared to hematological and GI
manifestations). Nonetheless, these injuries can also be
severe and lead to death (138, 139). Pneumonitis and
subsequent drop in blood oxygen levels are seen in COVID-
19 patients (98, 123, 140), as well as after irradiation, which
often progresses to pulmonary fibrosis (36, 139). As with
lung damage seen in COVID-19 patients, fibrosis was also
seen in long-term follow-up of Middle East respiratory
syndrome (MERS) patients (141). An increase in local
neutrophils, cytokines and other immune factors is seen in
COVID-19 patients with lung damage (32, 33), and also in
patients and animal models of acute radiation exposure (34–
36). These factors may also contribute to pneumonitis and
provide further support to the hypothesis that lung injury
seen in COVID–19 patients may progress to lung fibrosis.
While pulmonary symptoms are the most common in
COVID-19 patients, GI symptoms are also common.
Nausea, vomiting and diarrhea are all common symptoms
in both COVID-19 and irradiated patients. In one published
study of 651 patients in China, it was found that 11.4% of
patients experienced at least one GI symptom (142) while in
another study, 5% and 3.8% of hospitalized COVID-19
patients experienced nausea/vomiting and diarrhea, respec-
tively (143). Additionally, SARS-CoV-2 RNA is often
found in stool samples of patients with and without GI
symptoms (144), which is not surprising given that ACE2 is
expressed throughout the intestines and co-expressed with
TMPRSS2 in enterocytes in the ileum and colon (124). In
addition, SARS-CoV-2 was recently found to infect enter-
ocytes in vitro (145). The intestinal damage and symptoms
seen in COVID-19 do not appear to be as extreme as those
observed in GI-ARS, where crypt stem cells die, leading to
loss of GI function and integrity, causing not only nausea,
vomiting and diarrhea, but also hemorrhage, endotoxemia,
bacterial infection and even death (34, 146). However, the
involvement of the gut microbiota should not be overlooked
in either disease process. While the effect of SARS-CoV-2
infection on the gut microbiome is not yet known, a healthy
gut microbiome may have contributed to a successful, but
not overly-inflammatory immune response and expedited
recovery with other respiratory diseases (147). Interestingly,
fecal microbiota transplants have been shown to increase
survival in a lethal irradiation mouse model (148).
Another organ of concern is the heart. Though the
coagulopathy seen in both COVID-19 and ARS may
contribute to cardiomyopathy and circulatory failure, direct
cardiac tissue remodeling is also seen in both disease
processes. Cardiac ischemia, inflammation, fibrosis and
wall thickening have been noted in COVID-19 patients
(149, 150) and after irradiation, though dependent upon
dose and time after irradiation (151, 152). SARS-CoV-2
infection and radiation both increase risk of myocardial
infarction, with one study from China reporting that 7% of
case fatalities had only myocardial damage and circulatory
failure without respiratory failure (137). Studies of A-bomb
survivors have shown that cardiovascular disease risk
increases 14% per Gy of exposure (153). The short- and
long-term effects of cardiac damage from both disease
processes is a concern.
Additionally, symptoms indicating damage to the central
nervous system have been observed in patients with
COVID-19 and those with ARS. Headache, disorientation,
cognitive dysfunction, ataxia, seizures, unconsciousness, as
well as other symptoms have been reported in patients who
received lethal high-dose radiation (135) and in adult and
juvenile COVID-19 patients (126, 154, 155). Radiation
causes vascular damage and inflammation leading to
hemorrhage and edema (156) and can increase risk of
stroke (157). Similarly, brain damage in COVID-19 could
be due to systemic inflammatory response and coagulopa-
thy, leading to stroke and other issues (158), or may be
directly due to infection of brain tissue, as SARS-CoV-2
RNA has been found in cerebrospinal fluid and in brain
tissue after autopsy (159). Brain damage due to SARS-
CoV-2 infection or irradiation can initiate or exacerbate
injury to other organs, including respiratory or circulatory
failure (159). Additionally, there is some evidence that
radiation exposure may cause long-term psychological
issues (160), and given the similarities between radiation-
induced central nervous system inflammation and coagu-
lopathy and that seen in COVID-19, long-term neurological
and psychological effects may be forthcoming.
Several published studies have outlined the cutaneous
manifestations of COVID-19. These symptoms appear at
different time points of the disease progression, either at
onset of disease or after hospitalization (161), and depend
on the severity (mild or severe) of the infection (162–164).
The most common symptoms identified in patients with
mild infections are chilblain-like eruptions (i.e., COVID
fingers or toes), and petechiae/purpuric rashes, while
patients with severe infections experience symptoms such
as acro-ischemia with finger and toe cyanosis, cutaneous
bullae, dry gangrene, chickenpox-like rash and maculopap-
ular lesions (162). Like COVID-19, cutaneous manifesta-
tions from ARS depend on the timepoint and severity of
exposure often assessed using a graded scale set forth by the
National Cancer Institute (165). The most common
symptoms are also the least severe, i.e., acute radiation
dermatitis and mild erythema, and are seen in patients
exposed to low-dose radiation. These complications usually
present within 90 days of radiation exposure (165).
Radiation-induced telangiectasias, keratoses, ulcers, hem-
angiomas, splinter hemorrhages in the distal nail bed,
lentiginous hyperpigmentation and severe subcutaneous
fibrosis may also occur. High-dose radiation exposure leads
to severe symptoms such as moist desquamation and
ulceration (165). Of note, these or similar injuries may
occur in the oral epithelium in both COVID-19 (166, 167),
and after radiation exposure (168). In comparing cutaneous
manifestations related to COVID-19 and ARS, the symp-
toms associated with ARS are more severe and long lasting.
Delayed effects can be seen months to years postirradiation,
REVIEW 7
while lesions due to COVID-19 infection appear to heal
more quickly, usually within a few days (161, 169). On the
other hand, vascular complications associated with COVID-
19 infection closely resemble mild radiation burns seen in
patients that have been exposed to mild (non-lethal) doses
of radiation. In both COVID-19 and mild radiation
cutaneous injury, vascular injury may be further contribut-
ing to the skin injury, and damage to the vasculature in the
upper layers of the skin may be involved (162, 163, 169).
Other symptomatic overlaps between COVID-19 and
radiation exposure include: acute kidney injury (72, 170–
172), whether coagulopathy-related or direct, as renal tubule
cells are a potential target for SARS-CoV-2 (173); liver
injury, though more severe and possibly fibrotic in radiation
hepatitis (174) compared to the usually mild elevation of
aspartate aminotransferase and alanine aminotransferase
levels seen in 14–53% of COVID-19 patients (175); and
conjunctivitis (127, 176, 177), an immediate effect of
radiation with possible long-term effects including macular
degeneration and cataracts (178, 179). Fertility issues have
been seen in irradiated individuals, and there is concern
regarding male fertility in COVID-19 patients as well, as
ACE2 receptors are also expressed in the testis, and some
male patients have reported scrotal discomfort. Nonetheless,
SARS-CoV-2 has yet to be found in semen, and this disease
may still be too new to identify fertility issues (180). High
rates of androgenetic alopecia in hospitalized COVID-19
patients have been documented, leading to the hypothesis
that the use of anti-androgen therapy (flutamide) may be a
possible treatment for COVID-19 patients (181).
Radiation-induced coagulopathies (RIC) are part of the
continuum of the irradiation sequalae (134, 182, 183), with
parallels to DIC. Hemorrhage, a hallmark of DIC, was
reported in 60% of the mortalities in the A-bomb-exposed
population, accompanied by petechial lesions and throm-
bocytopenia (184), and was also observed after (184), as
well as other radiation accidents (185, 186). Prevalence of
prolonged clot formation times, increased levels of
thrombin-antithrombin III (TAT) complex and increased
circulating nucleosome/histone (cNH) levels were noted in
blood from irradiated clinical samples (134). D-dimer has
not been reported in any of the radiation-related coagulop-
athy studies, but other metrics used to predict coagulopathy
for COVID-19 are similar to RIC. Though in many systems
radiation damage is much more severe and chronic, overall,
the similarities noted thus far between COVID-19 and ARS/
DEARE may provide insight into the late effects of
COVID-19, as well as shed light on possible targets for
diagnostics, prognostic markers and therapeutics.
MEDICAL COUNTERMEASURES
As noted, there are clear parallels between radiation
exposure, which is known to act systemically to cause
damage, and COVID-19, which has been implicated in
organ damage ranging from the lung and GI tract to the
heart, brain, kidney and vasculature. In fact, the character-
istics of radiation-induced pneumonitis are similar to SARS-
CoV-2 interstitial pneumonia (187). Therefore, it is not
surprising that there are a number of treatments for radiation
exposure under development that could prove to be
efficacious for COVID-19. Because it is not possible to
‘‘fight’’ radiation in a conventional sense, in the way that it
is possible to develop approaches directly targeting a
pathogen, researchers have relied instead on modifying the
host response to injury, to identify therapies to address
damage caused by exposure to radiation. In many cases,
these approaches have worked by harnessing the body’s
innate immunity, which is often dysregulated by radiation
exposure. These treatments fall into several general
categories, which include anti-oxidants, anti-inflammato-
ries, antibiotics, anti-fibrotics, growth factors, cellular
therapies, and products that target the vasculature or the
RAS. Especially important to emphasize is the ability to
repurpose these kinds of established drugs, some of which
are already in clinical use, to expedite their use in patients
with SARS-Cov-2 infection. These varied approaches will
be considered separately below, according to their mecha-
nisms of action.
Growth Factors
COVID-19 is characterized by damage to the lung and
vasculature, reducing blood oxygenation. In a review of the
effects of erythropoietin (EPO), Ehrenreich et al.(188)
noted that EPO acts on tissues beyond erythropoiesis; these
effects could be brought to bear in fighting SARS-CoV-2
pathology. EPO is produced in the body in response to low
oxygen levels, and in the short term, binds to receptors in
the brain stem to improve mechanical ventilation. EPO also
acts on airways and lung vasculature to reduce inflamma-
tion and promote vascularization and has been shown
clinically to be neuroprotective. Although at this writing, no
trials have been started, a randomized placebo-controlled
trial for proof-of-concept has been proposed. EPO has also
been shown to accelerate the expansion of erythroid
progenitors in mouse irradiation models (189, 190). Galal
et al.(191) described the effects of EPO beyond
erythropoiesis, through the reduction of oxidative stress
via upregulation of anti-inflammatory receptors. These
activities point to possible treatments to reduce inflamma-
tion contributing to radiation-induced GI, lung, or kidney
injury.
Leukinet(sargramostim or granulocyte-macrophage col-
ony-stimulating factor, GM-CSF; Partner Therapeutics Inc.,
Lexington, MA) is one of three leukocyte growth factors
approved by the U.S. FDA for treatment of ARS (192).
Lang et al.(193) noted that, just as immune system
stimulation can either help the body fight a viral infection or
produce a deleterious inflammatory response, administra-
tion or inhibition of GM-CSF may be useful therapies for
COVID-19. Lung macrophages depend on alveolar GM-
8RIOS ET AL.
CSF production for their maintenance, and GM-CSF
administration could provide protection against viral infection
in the early stages of ARDS and promote tissue repair. At this
writing, sargramostim is being proposed as a therapeutic
against COVID-19 in three trials
7
(NCT04400929,
NCT04326920, NCT04411680). As for deleterious effects,
GM-CSF can exacerbate the inflammatory response, driving
lung pathologies such as those resulting from COVID-19. In
this case, GM-CSF inhibition could reduce expression of the
pro-inflammatory cytokines IL-1, IL-6 and TNF, providing a
multi-pronged approach to dampen an overstimulated im-
mune system. Monoclonal antibody treatments targeting GM-
CSF or GM-CSF receptor that are ongoing include: otilimab
(NCT04376684), gimsilumab (NCT04351243), lenzilumab
(NCT04351152), TJM2 (NCT04341116) and mavrilimumab
(NCT04397497, NCT04399980, NCT04447469). Namilu-
mab is being used in the clinic in an expanded access
program. Patients receiving treatment in these experimental
protocols will need to be monitored carefully because of the
role that GM-CSF plays in immunological homeostasis. In
addition, it would appear that the timing of these kinds of
growth factor interventions is critical to their potential
efficacy.
Antioxidant Approaches
Radiation-induced damage is characterized by increases
in reactive oxygen species (ROS) and oxidative stress (194–
196). These increases, and the resulting inflammatory
response, can damage other sensitive tissues (197–200).
The antioxidant N-acetyl cysteine (NAC) has been shown to
mitigate radiation-induced damage to the GI tract and
improve 10- and 30-day survival in mice receiving total-
abdominal irradiation (201). NAC also decreased out-of-
field bone marrow damage and ROS levels, suggesting that
bone marrow damage contributes to some of the radiation-
induced GI injury. Because of similar patterns of tissue
damage, Corry et al. hypothesized that COVID-19-induced
damage to the lung could also be ameliorated by NAC
treatment (202). This hypothesis was further supported by
an earlier finding that NAC treatment of patients with acute
lung injury and ARDS resulted in reduced mortality (203).
Currently, there are several ongoing national clinical trials
to address the possible benefit of NAC treatment in
COVID-19 patients (NCT04374461, NCT04419025,
NCT04370288 and NCT04279197).
Another compound under investigation for COVID-19 is
the histamine H2-receptor antagonist famotidine. Typically
used to treat acid reflux and heartburn, the drug is also
known to have antioxidant activity (204). Although an
unlikely candidate to treat viral disease, famotidine first
came to the attention of researchers interested in repurpos-
ing already-licensed products (205). Generic and off-patent
drugs were of particular interest because of their safety and
affordability, supported by extensive data in humans (206).
In addition, in silico analysis suggested that the drug could
be useful as a therapeutic alternative in COVID-19 (207).
Clinicians have noted that hospitalized patients taking the
drug for other medical indications appeared to recuperate
from COVID-19 better than those who did not take the drug
(208). A review of over 6,000 patient records suggested that
famotidine use led to a death rate of ;14%, compared to
27% for those who had not taken famotidine. This finding
was further supported by a retrospective analysis of
COVID-19 patients who received the drug within 24 h of
hospital admission, which showed that its use reduced the
risk of intubation or death (209). One suggested mechanism
of action of famotidine is a direct action on the receptor,
leading to improved mast cell regulation (210). Additional,
prospective clinical trials to look at the efficacy of the drug
in COVID-19 patients are underway (NCT04370262,
NCT04389567). A recently published article has suggested
that famotidine is ineffective; however, the authors state that
‘‘We’re not challenging that famotidine might help. We’re
saying that the mechanism of action is not antiviral’’.
8
This
is consistent with the primary proposed antioxidant
mechanism of action.
Radiation researchers have also sought to understand the
protective effects of famotidine administration, with regards
to limitation of DNA damage and cellular protection. With
studies performed in vivo, in both pre-clinical irradiation
models as well as in patients undergoing radiotherapy, the
potential benefits of the drug have been demonstrated.
Famotidine was found to be radioprotective in mice that
were administered the drug prior to irradiation, as assessed
by micronuclei formation in cells of the bone marrow (211,
212). Pre-clinical work with mouse leukocytes collected
from irradiated animals documented consistent outcomes,
with reductions in DNA damage in animals treated with
famotidine prior to irradiation (213). Famotidine also
significantly reduced lymphocytopenia in prostate cancer
patients who received the drug a few hours prior to
undergoing radiotherapy (214). In another study, prostate
cancer patients given twice-daily oral doses of famotidine
during their radiotherapy led to a reduction in radiation-
induced injury to the normal rectal tissue (215). These
clinical findings in cancer patients were based on earlier
work using peripheral blood samples taken from normal
healthy volunteers (216). In those studies, blood was
irradiated ex vivo in the presence or absence of vitamin C
and famotidine. Comet assay results suggested that the
presence of famotidine was protective for radiation-induced
apoptosis, with an estimated dose reduction factor of 1.5.
The protective effects of the drug noted above suggest the
drug may have an antioxidant effect and ability to scavenge
7
NIH/U.S. National Library of Medicine. ClinicalTrials.gov.
(https://clinicaltrials.gov/)
8
Saey TH. A popular heartburn medicine doesn’t work as a
COVID-19 antiviral. ScienceNews 2020. (https://bit.ly/2ZSFtDi)
REVIEW 9
free radicals, a mechanism that would justify clinical use of
the drug for COVID-19.
Anti-inflammatory Approaches
Severe COVID-19 is characterized by a cytokine storm,
indicative of an overactive immune response to the infection
(217). Because elevated levels of pro-inflammatory cyto-
kines are associated with high morbidity and mortality,
various approaches to modulate the inflammatory response
have been proposed. Specifically, COVID-19 results in
elevated levels of serum IL-6 (217). The IL-6 receptor
antagonist, tocilizumab (Actemrat, Genentech, San Fran-
cisco, CA), indicated for rheumatoid arthritis, has also been
proposed to ameliorate radiation-induced tissue damage,
and has shown efficacy in diminishing the cytokine storm
resulting from cancer immunotherapy (218). In early
published clinical studies to assess the potential impact of
tocilizumab treatment in COVID-19, Somers et al.(219)
performed a single-site trial of the drug in 154 COVID-19
patients on mechanical ventilation. Treatments resulted in a
lower hazard of death, although the rate of superinfections
increased. Antinori et al.(220) noted the risk of a secondary
Candida infection from tocilizumab treatment, and therefore
suggested that the drug only be used in well-designed
clinical trials. Currently, a tocilizumab treatment arm has
been included as part of the University of Oxford’s
Randomised Evaluation of COVID-19 Therapy (RECOV-
ERY) trial,
9
the results of which have not been made
available at the time of this writing. In a study looking at the
effect of the drug in critically ill patients, treatment led to
improved oxygenation and blood counts (221). In addition,
another anti-IL-6 receptor antibody, sarilumab (Kevzarat;
Regeneron Pharmaceuticals Inc., Tarrytown, NY and
Sanofi, Paris, France) is also under clinical consideration
in more than 10 registered trials as a treatment for late-stage
COVID-19 patients.
Dexamethasone is a generic corticosteroid drug, which is
licensed for a broad range of indications including arthritis,
allergic reactions and immune system disorders. Dexameth-
asone has been shown to reduce multi-organ damage,
including lung injury, in rats that have been exposed to
localized radiation (222). In non-human primate (NHP)
models of radiation-induced lung injury, dexamethasone has
been used as a component of the medical management,
where it is given when there is an increase in the non-
sedated respiratory rate, which suggests respiratory distress
(138, 223, 224). This use of the drug is similar to its clinical
use for dyspnea (225). In these NHP studies, dexametha-
sone treatment reduced the elevated respiratory rate, lung
density, pleural effusion and pneumonitis, leading to
improved outcomes. Dexamethasone treatment has also
been included as an arm in the RECOVERY trial (226),
where its use has been shown to reduce COVID-19
mortality from 40.7% to 29% among patients who required
invasive mechanical ventilation, but did not appear to confer
a benefit to hospitalized patients who received only oxygen.
These data suggest that corticosteroid treatment may only be
effective if the immune system is overstimulated to the
extent that it is causing significant harm. The WHO Rapid
Evidence Appraisal for COVID-19 Therapies Working
Group performed a meta-analysis of seven randomized trials
and concluded that systemic corticosteroids reduced 28-day
all-cause mortality (227). Another treatment that has been
shown to improve survival in a mouse model of radiation-
induced lung injury is BIO 300 (Humanetics Corp., Edina,
MN), which is a nanosuspension of the soy isoflavonoid,
genistein. In mice, BIO 300 administration improved
survival and reduced other morbidities caused by lung
irradiation (228). Although genistein has antiviral activity
(229–231), it may also be useful to prevent radiation-
induced lung damage. Genistein is thought to act through
inactivation of NF-jB(232), and since NF-jB inhibition
has been shown to reduce inflammation in a mouse model
of COVID-19, it could be effective in treating lung
complicationscausedbySARS-CoV-2infection.Hu-
manetics has announced initiation of a clinical trial in
discharged COVID-19 patients, to determine if treatment
with the oral BIO 300 product can reduce late lung fibrosis
and improve quality of life in patients who are recovering
from the infection (NCT04482595).
Given that the autoimmune disease, rheumatoid arthritis
(RA) is caused by an overactive immune response that
targets normal joint tissue, it is not surprising that
approaches that have shown benefit in RA are being
considered for COVID-19. For example, anakinra (Kine-
rett; Swedish Orphan Biovitrum AB, Stockholm, Sweden),
a specific IL-1 receptor antagonist, has been proposed as a
possible treatment. Similarly, anakinra has been reported to
reduce vascular inflammation in a mouse model of radiation
exposure (233). In that study, administration of the drug for
two weeks postirradiation reduced the expression of
inflammatory mediators such as pro-caspase and caspase-
1. In an early case report from Italy, clinicians described a
critically ill patient who was successfully treated with
anakinra (234). Other studies have since followed; in fact,
King et al. have described ten ongoing clinical trials that
target hyper-inflammation. It is clear that many different
dosing regimens are being tested and that most of these
smaller studies (,400 patients) should be considered
preliminary, but data arising from these studies could lead
to larger-scale studies with more uniform treatments. The
outcomes of some of these anakinra studies have been
published. In the anakinra-COVID study performed in
France, 25% of patients who were treated with anakinra
required invasive mechanical ventilation or died, compared
to 44% of historical controls from the same hospital (235).
In another small retrospective cohort study from Italy, part
of the COVID-19 Biobank study, anakinra-treated patients
9
RECOVERY/Randomised Evaluation of COVID-19 Therapy.
Oxford, UK: University of Oxford; 2020. (https://www.recoverytrial.
net/)
10 RIOS ET AL.
showed improvement in respiratory parameters (reduced
need of supplemental oxygen, improved PaO
2
/FiO
2
ratio)
and reductions in the inflammatory marker, C-reactive
protein.
Anti-fibrotic Approaches
Lung inflammation caused by radiation can progress to
fibrosis in later stages of injury, causing shortness of breath
and reduced blood oxygen saturation. Drugs currently
approved to treat lung fibrosis include nintedanib (OFEVt;
Boehringer Ingelheim, Ingelheim am Rhein, Germany) and
pirfenidone (Esbriett; Genentech). Nintedanib is a tyrosine
kinase inhibitor approved for idiopathic pulmonary fibrosis.
Using a mouse model of localized irradiation, researchers
demonstrated that nintedanib protected against long-term
fibrosis, as detected microscopically at 39 weeks postirra-
diation (236). Similarly, studies showed protection in a
mouse model of thoracic irradiation by pirfenidone
treatment (237). In terms of COVID-19 and its progression,
it was noted that patients who experienced severe ARDS
often exhibit later lung fibrosis (238). Although anti-
inflammatory treatments could prevent late-stage disease,
it is not known if this will be the case for COVID-19. For
this reason, the authors propose that anti-fibrotics, such as
those described above, should be studied in clinical trials. In
one clinical study (NCT04338802), patients will be
randomized into a placebo-control or nintedanib treatment
group, and in another, the safety and efficacy of pirfenidone
will be studied in patients with SARS-CoV-2 infection
(NCT04282902). Similarly, imatinib (Gleevect; Novartis,
Basel, Switzerland), licensed for chronic myeloid leuke-
mia,
10
and previously shown to increase the survival time of
irradiated mice by delaying lung disease, has been
suggested as a COVID-19 treatment (239). Several clinical
trials are planned (NCT04357613) or recruiting
(NCT04394416) patients to study the drug as a possible
treatment for the disease.
Pentoxifylline is another drug that could potentially be
repurposed as a treatment for COVID-19. Originally
licensed to treat pain in individuals suffering from
intermittent claudication (peripheral arterial disease),
11
pentoxifylline improves blood flow, thereby increasing
tissue oxygenation. It has also been shown to inhibit
synthesis of pro-inflammatory cytokines, specifically TNF-
a(240). Pentoxifylline has been shown to reduce radiation-
induced fibrovascular injury in animal models (241) and in
the clinic (242). Because of these anti-fibrotic (and anti-
inflammatory) activities, pentoxifylline has been proposed
as a possible preventative of COVID-19 complications
(243) and will be tested in a clinical trial (NCT04433988).
Another driver of pulmonary fibrosis, TGF-b(244),
presents a potential target for the prevention of pulmonary
fibrosis in COVID-19 patients (245). For example, an anti-
sense mRNA product that targets TGF-b2 production, OT-
101 (Mateon Therapeutics, San Francisco, CA), is in phase
3 trials for several cancers, and has been proposed as a
COVID-19 treatment (246). Given the probable involve-
ment of TGF-bin the progression of COVID-19, a
preclinical, anti-TGFbreceptor 1 product, IPW5371
(Innovation Pathways, Palo Alto, CA) may also be a
promising candidate to treat COVID-19-induced lung
fibrosis, as it has previously been shown to reduce fibrosis
and improve survival in a mouse model of radiation
exposure (247).
RAS-Targeted Approaches
In the early stages of the pandemic, it became clear that
one method by which the SARS-CoV-2 virus gained access
to the internal cellular machinery was via the ACE2
receptor, the expression of which is most prevalent on lung
alveolar epithelial cells (248). This finding was similar to
SARS-CoV, which also used the ACE2 receptor to gain
entry into cells (249). Therefore, initial treatments consid-
ered for patients were angiotensin-converting enzyme
inhibitors (ACEIs) or angiotensin II type receptor blockers
(ARBs). Because many drugs, such as angiotensin-convert-
ing enzyme inhibitors (ACEIs), are generic and widely
available, they represent a valuable option in repurposed
drugs. Clear benefits include low cost, wealth of clinical
experience, established human data and minimal side
effects. During the initial stages of the COVID-19 response,
it was thought that individuals currently taking hypertensive
drugs could be at an increased risk of infection, and
therefore, their use should be discontinued in COVID-19
patients (250, 251). In one large retrospective study of over
12,000 patients, the relationship between prior use of ACEIs
and patient outcomes after infection was considered, with
the finding that there was no correlation between prior
hypertension medication use and COVID-19 risk (252).
In addition, it became evident that certain segments of the
population were more likely to have more severe forms of
disease and a propensity to develop ARDS. These
individuals included those with cardiovascular disease,
diabetes and hypertension, all of which have associations
with dysregulated aspects of RAS (253). Still other studies
suggested that these drugs should be considered as a
potential treatment due to their multi-prong effects (e.g.,
anti-inflammatory anti-oxidant and antifibrotic) (254).
Therefore, there remains a need to evaluate both angiotensin
agonists and antagonists for COVID-19 (255). In one study,
COVID-19 patients with hypertension were enrolled, to
explore if the use of ACEI or angiotensin receptor
antagonist treatments would impact the severity and
progression of the infection (256). As a biomarker of
10
Gleevec (imatinib mesylate) tablets for oral use. Prescribing
information. Stein, Switzerland: Novartis Pharma Stein AG; East
Hanover, NJ: Novartis Pharmaceuticals Corp.; 2008. (https://bit.ly/
3kyuqan)
11
Trentalt(pentoxifylline). Reference ID: 3873773. Parsippany,
NJ: Validus Pharmaceuticals LLC; 2016. (https://bit.ly/2ZYT6Rz)
REVIEW 11
efficacy, serum levels of IL-6 and circulating T-cell counts
were also evaluated. Both treatments were found to increase
T cells, decrease viral load and IL-6 levels, and reduce the
severity of the course of the disease. Therefore, the
recommendation was made to maintain ACEI and angio-
tensin receptor blocker treatments in patients with COVID-
19.
Similarly, the radiation community has established the
role that products targeting RAS can play on the progression
of radiation-induced organ injuries, primarily the lung and
kidneys. Many studies have demonstrated the ability of
ACEI products to address radiation-induced lung injuries.
Primarily conducted in rat models of injury, ACEIs were
found to increase survival and decrease lung, kidney and
vascular damage (257, 258). These findings were consistent
across different methods of radiation exposures, such as TBI
plus bone marrow transplant (BMT), whole-thorax lung
irradiation (WTLI), or partial-body irradiation (PBI) with a
percentage of the bone marrow spared using shielding
(259). Mitigation of lung and kidney injuries was
determined through assessment of circulating markers of
renal damage (e.g., blood urea nitrogen and creatinine) and
CT imaging of lungs in irradiated animals. In an irradiated
rat model, captopril and fosinopril both increased survival
after 11 Gy (TBI with BMT) and decreased lung injury
(257). Similarly, lisinopril was found to mitigate kidney
(260) and lung (259) damage after high-dose PBI in adult
rats and improve survival in juvenile and geriatric rats (38).
Enalapril mitigated injury and improved survival in a WTLI
rat model, even when initiated 35 days postirradiation (261).
Captopril, administered in a TBI model, improved survival,
although that benefit was diminished when coupled with
skin trauma (262). Finally, ramipril mitigated radiation-
induced damage to the spinal cord (263). In other preclinical
models of radiation injury, angiotensin (1–7) [A(1–7)], a
component of the RAS mentioned above, has also been
studied for its ability to improve survival in irradiated
rodents (264, 265). These peptides, which have been shown
to alter activity in many cell types, accelerated recovery of
the bone marrow in mice receiving TBI, and also improved
the platelet nadir in the animals (264). In later studies,
angiotensin peptides, even when administered days post-
lethal irradiation, improved mouse survival and reduced
bleeding time (265).
Approaches Targeting the Vasculature
The ability of the virus to directly infect and dysregulate
endothelial cells (41) is the driving force behind vascular
coagulopathies and thromboses observed in COVID-19
patients. In addition to vascular effects resulting from direct
viral infection, COVID-19 patients have been found to have
higher levels of VEGF as compared to healthy controls (266).
Elevated VEGF could further increase vessel permeability,
leading to some of the symptoms noted in patients.
Furthermore, studies have implicated VEGF as a target for
therapeutic intervention in ARDS (267). At the time of this
writing, several clinical trials of COVID-19 patients are being
planned or are recruiting to assess the potential efficacy of
bevacizumab, an anti-VEGF, long-lived, humanized mono-
clonal antibody, as a treatment for COVID-19-associated
ARDS (NCT04275414, NCT04344782, NCT04305106).
Also known as Avastint, the mechanism of action of the
drug is to bind to extracellular VEGF and prevent its
interaction with its receptor on endothelial cells (268).
Radiation exposure has long been known to lead to
vascular impairment, which is believed to explain the multi-
organ dysfunction that it causes (121). Many promising
clinical approaches that target the vasculature could have an
effect on radiation-induced damage. VEGF also represents a
molecule that is involved in radiation exposure, and thus, is
a target for reducing the negative effects. For example,
VEGF levels have been shown to be increased in mice after
irradiation (269, 270), and elevated levels of the growth
factor have been implicated in the development of radiation-
induced necrosis of normal tissue (271). Anti-VEGF
antibodies (bevacizumab) have been shown to mitigate
radiation necrosis in mouse brains (272), and in rats that
underwent gamma-knife radiosurgery (273), and bevacizu-
mab has been used in the clinic for radiation injury, where it
was found to reduce necrosis in nasopharyngeal carcinoma
patients who received radiotherapy (274).
As observations continue to be made in COVID-19
patients, it has become apparent that DIC may be
responsible for many of the complications that have been
seen (275–278). This condition, which is characterized by
the development and circulation of small blood clots, can
lead to the blockage of small vessels. As a follow-on effect,
the abnormal consumption of platelets can, in turn, lead to
thrombocytopenia and hemorrhage (279). In several animal
models of lethal radiation exposure, including ferrets (280)
and Yucatan minipigs (281), there has been evidence of
DIC, both in the early days after irradiation and at the time
of death. It is believed that DIC could be a contributor to
radiation-induced human mortality (50), as hemorrhage at
time of death has been seen clinically in irradiated patients.
A major finding in autopsies of humans who have died from
radiation exposure (282), widespread bleeding in the tissues
often occurs as a result of DIC. Coagulation abnormalities
have also clearly emerged as a key hallmark of COVID-19
infections (283). In addition to thromboses (284), throm-
bocytopenia has also been noted in some patients
experiencing COVID-19 infection. In a study from China
involving over 1,000 patients, 36.2% were thrombocytope-
nic, a finding that was greater in cases that were more
advanced (98). This association of low platelet count with
the infection is also supported by a meta-analysis in which
data from nine studies were examined, involving nearly
1,800 patients (71). Those researchers found that platelet
counts were much lower in patients with severe disease and
concluded that these lowered counts could indicate an
increased mortality risk. It is postulated that infection with
12 RIOS ET AL.
SARS-CoV-2 leads to this dysregulated platelet state via a
number of different causative pathways, including a
reduction in platelet production due to loss of progenitors
and growth inhibition, increased clearance due to evolution
of autoantibodies, and enhanced platelet consumption due
to lung injury, which leads to platelet activation and
formation of microthrombi (284).
Like COVID-19, radiation exposures, especially TBI,
are known to lead to a reduction in platelet levels. This
thrombocytopenia has been postulated to play a major role
in deaths from exposure (282). To address this manifes-
tation of radiation injury, drugs that promote platelet
production and are FDA-approved for other indications
[e.g., immune thrombocytopenic purpura (ITP)] have been
tested to see if they could mitigate damage and improve
survival. This has included preclinical and clinical studies
of drugs such as Nplatet(Amgen, Thousand Oaks, CA)
(6, 285), and Promactat(Novartis) (286, 287). Although
there is a case report documenting use of Promacta to treat
a COVID-19 patient who presented with ITP symptoms
while hospitalized (288) and responded well to the
treatment, it does not appear that these therapies have
been attempted on a broader scale thus far. This may be
due to the delicate balance between thrombocytopenia and
thrombosis in these patients; timing of interventions is
crucial to their efficacy or detriment. According to case
reports, heparin has been administered as a means of
countering hypercoagulation (289), and the International
Society of Thrombosis and Haemostasis is now recom-
mending use of heparin for all COVID-19 patients (290).
Clearly, clinical decisions concerning the use of treatments
that either enhance platelet counts or seek to reduce
clotting are complex, and the use of these kinds of
treatments represents an area of great interest. TP508, a 23
amino acid peptide that is a truncated form of human
prothrombin, has also been shown to mitigate radiation
normal tissue injury and increase survival in a mouse TBI
(LD100/15) model (291). Under study in a number of
other preclinical models [e.g., ischemia (292)and
musculoskeletal injuries (293), and in clinical trials to
address diabetic foot ulcers (294)], TP508 has been shown
to enhance tissue repair by targeting endothelial cells
(292). This product is in early preclinical testing as a
treatment for COVID-19
12
because it targets the vascula-
ture as its primary mechanism of action and has
generalized ability to mitigate tissue damage.
Statins as a Common Treatment for Vascular Injury
Statins represent another area of drug treatment overlap
between radiation and COVID-19 (295, 296). In addition to
an anti-inflammatory effect, statins may modify the entry of
viruses into cells, inducing autophagy of infected cells or
altering activation of the coagulation cascade (297). In silico
studies suggest that statins possess direct antiviral activity
through blocking infectivity (298) and have been shown to
enhance ACE2 levels (299) and protect against ARDS
(300).
In clinical trials of COVID-19 patients, observed benefits
were suggested to outweigh their potential risk (301). A
retrospective study of patients treated with statins for other
indications while hospitalized with COVID-19 showed a
lower risk of mortality (302). In animal models of radiation
injury, statins have demonstrated damage mitigation to
normal tissues. Simvastatin, a HMG-CoA reductase inhib-
itor with widespread clinical use, has been shown to
mitigate lung injury in a high-dose thoracic irradiation
mouse model (303), and protects the GI tract, bone marrow
(304) and salivary glands (305). Similarly, atorvastatin
limits radiation-induced heart damage in a rat model (306)
and kidney injury in mice (308).
Perhaps most significant, in terms of overlap with a
primary mechanism of action involved in COVID-19,
atorvastatin has been shown to induce a protective response
in irradiated human umbilical vein endothelial cells
(HUVECs) (308). Treatment of HUVECs with atorvastatin
decreased radiation-induced cell apoptosis, thought to be
driven by upregulation of thrombomodulin and protein C
activation. Finally, lovastatin, when administered after high-
dose irradiation in a WTLI mouse model, increased
survival, reduced levels of macrophages and lymphocytes
in the lung and decreased collagen (309). Activated protein
C (APC) has been tested for its ability to mitigate radiation
injuries (310) and has now been proposed as a therapy for
the vascular dysfunction and abnormal thrombosis (e.g.,
DIC) observed in COVID-19 patients (311). APC’s ability
to downregulate inflammation and generate thrombin
indicates its potential to reduce inflammation and limit
ischemic injury throughout the body.
Antibiotic Treatments for Radiation or SARS-CoV-2
Infection, beyond Antibacterial Properties
Given the need to rapidly assess potential treatments,
many clinicians have turned to antibiotics, which have the
advantage of safety data and clinical experience. Several
classes of antibiotics, which have activity against secondary
bacterial infections and have anti-inflammatory and antiviral
properties, have been suggested as potential treatments for
COVID-19. In silico modeling and other predictive studies
indicate efficacy of aminoglycoside compounds such as
streptomycin (312); tetracyclines, such as doxycycline (313,
314) and eravacycline (312); macrolide antibiotics, such as
azithromycin (315); streptogramins, such as quinupristin
(316); polyether ionophoric antibiotics, such as salinomycin
(317); and glycopeptides, such as teicoplanin. Teicoplanin,
a drug used to treat Staphylococcus infections, was found to
be effective against MERS and is predicted to also be
12
Chrysalis BioTherapeutics receives funding from the National
Institutes of Health for COVID-19 therapeutic development.
Galveston, TX: Chrysalis BioTherapeutics Inc.; 2020. (https://bit.
ly/2HkvCQm)
REVIEW 13
effective against SARS-CoV-2 (318, 319). There was hope
that azithromycin, in combination with hydroxychloroquine
(320), might be effective in reducing the severity of SARS-
CoV-2 infections (321). The drug, commonly used to treat
respiratory and other infections, is thought to strengthen
interferon-mediated antiviral responses (315). Unfortunate-
ly, clinical studies did not provide evidence of efficacy of
the drug (322). In contrast, some studies suggest limited
benefit from the use of antibiotics, either alone or in
combination (323) in both children and adults with COVID-
19 (324), and other research suggests that the use of some
antibiotics could actually worsen the progression of the
disease (325).
As with COVID-19, the efficacy of antibiotics, outside of
their normal antibacterial impact, have been observed in the
mitigation of radiation normal tissue injuries. In vitro
screening of a broad range of antimicrobial agents was
conducted to determine if any of these molecules could be
used a mitigators of radiation injury. In one screen that used
hematopoietic progenitor cells in a clonogenic survival
assay, tetracycline was identified as a significant mitigator
(326). In another in vitro screen of mouse lymphocytes, two
antibiotic classes, tetracyclines and fluoroquinolones (10
different molecules), were identified as potential radiation
mitigators, which the authors attributed to being separate
from their antibacterial properties. From these potential
mitigators, tetracycline showed efficacy in a TBI mouse
model of survival and further data mining confirmed these
earlier findings (327). The predicted impact of quinolones
on mitigation of radiation injuries was not surprising, given
earlier studies in mice that showed ciprofloxacin, sparflox-
acin and clinafloxacin could enhance colony-forming units
in the bone marrow and white blood cell counts in irradiated
mice (328). Similarly, a published study from 1961 showed
that the presence of chlortetracycline in rodent feed
decreased X-ray killing in mice (329). In more recent
studies, fluoroquinolones, such as ciprofloxacin and levo-
floxacin, as well as doxycycline, and neomycin, were all
found to increase the mean survival time in mice exposed to
lethal doses of radiation. Doxycycline and neomycin also
improved day-30 survival in the animals (330). In other
work, ciprofloxacin, an antibiotic notable for its efficacy in
treating bacterial pneumonia and other infections, was also
shown to enhance survival after radiation exposure in vivo
and in vitro. In studies using peripheral blood mononuclear
cells, ciprofloxacin protected against radiation exposure by
inhibiting p53 phosphorylation and increasing Bcl-2
production (331), and has also been shown to increase
survival in a mouse model of TBI (332).
Cellular Therapies
The development and use of cellular therapies, in both the
oncology clinic (333) and as a radiation treatment (334,
335), has long been an approach of interest. In particular,
mesenchymal stem (or stromal) cells (MSCs) have been
shown to mitigate the effects of radiation-induced lung
injury (336, 337). Stem cells, as well as extracellular
vesicles are also being considered as a means of treating
injuries caused by SARS-CoV-2 (338). Specifically, MSCs
derived from various sources, are under study to address
lung injuries in COVID-19 patients (339). These sources
include the bone marrow (340), umbilical cord (341),
adipose tissue (342), peripheral blood and placenta. Early
reported work indicates that the use of MSCs in patients is
safe, and their use is effective in improving lung functional
outcomes (343). There are more than 30 clinical trials
worldwide in which these cells are being used as COVID-19
treatments (clinicaltrials.gov). In fact, several cellular
therapies that are under active investigation for their
development as radiation normal tissue injury mitigators
are also showing promise as therapies in COVID-19 patient
trials. These trials include those for placental expanded
(PLX) cells
13
and multipotent adult progenitor cells (Multi-
Stemt; AthersystInc., Cleveland, OH).
14
CONCLUSIONS
The majority of SARS-CoV-2 infections are asymptom-
atic or symptomatically mild and do not require hospital-
ization. However, at the time of this writing, there are over
50 million confirmed infections worldwide, with more than
9 million confirmed cases in the U.S. alone, of which
hundreds of thousands have required hospitalization and
over 225,000 have died. While host factors such as
comorbidities, age and possibly genetics are strongly
associated with the severity of disease, it is clear that the
pathology of severe COVID-19 is characterized by a
dysregulated inflammatory response, the so-called ‘‘cyto-
kine storm,’’ along with a thrombotic response involving
elevated D-dimer levels and coagulopathies ranging from
small vessel thrombi to DIC. The cytokine storm is
manifested through high levels of pro-inflammatory cyto-
kines such as IL-1b, IL-6, IL-18, and TNFa.The
cumulative systemic effects of the hyperinflammatory
response and dysregulated thrombotic activity can lead to
multi-organ failure and death. In the current absence of any
effective prophylactic interventions, therapeutics capable of
beneficially altering these dysregulated processes and
supporting recovery are urgently needed.
A striking feature of the immune dysregulation, progres-
sion of disease and mechanisms of organ damage in COVID-
19 is its similarity to the biological responses to ionizing
radiation exposure at doses sufficiently large to cause ARS
(.2 Gy in humans). The similarity of inflammatory
responses and organ damages that are caused by COVID-
13
Pluristem provides 28-day follow up for ventilator-dependent
COVID-19 patients under compassionate use program in Israel and
U.S. Los Angeles, CA: GlobeNewswire, Inc.; 2020. (https://bit.ly/
3cjdzVX)
14
COVID-19 and other viral induced ARDS. Cleveland, OH:
Athersyst, Inc.: 2020. (https://bit.ly/33IsQMe)
14 RIOS ET AL.
19 and radiation offers an opportunity for possible COVID-
19 interventions. There is a wealth of data (detailed above)
and extensive experience from the field of radiation biology
for the development of radiation mitigators that target
radiation-induced dysregulation of inflammation, lung fibro-
sis and vascular damage that may lead to multi-organ failure
and death in a fashion similar to that seen in COVID-19.
Many of these agents are currently at preclinical levels of
development, but several are already licensed as radiation
mitigators and FDA approved for use in humans (Neupo-
gent, Neulastat,Leukinet), or have demonstrated safety in
human clinical trials for other indications, and are therefore
well-poised for possible translation to COVID-19 indications.
Finally, in perhaps the truest definition of overlap between
radiation and COVID-19, is the novel (and yet ‘‘old-school’’)
proposal, that low-dose radiation therapy (LDRT), involving
exposure of the thorax of the patient, may have efficacy in
countering lung infections, including those caused by SARS-
CoV-2 infection. This concept is based on studies on the use
of radiation exposures in the early 1900s, before the advent of
modern antibiotics, in which radiation was used to treat
pneumonias resulting from bacterial or viral infections (344).
This treatment proposal, however, is not without controversy.
Already, numerous editorials and comments have been
published (345–352) and discussion surrounding this treat-
ment modality will undoubtedly continue. Nonetheless,
LDRT is not considered to be a potential mitigator of high-
dose radiation damage to the lung, and therefore this
treatment generally falls outside the scope of the current
review.
While medical expertise in the fields of infectious disease,
pulmonology, immunology, rheumatology and hematology
are critical paths forward in the search for COVID-19
therapeutic interventions, the substantial overlap in patho-
biology between COVID-19 and ARS presents the
possibility of readily translatable, potentially high-impact
pharmacological interventions that were originally evaluat-
ed and/or developed to mitigate radiation injury in humans.
By the same token, it is possible that, given the broad range
of new treatment approaches that are being considered for
possible efficacy in COVID-19 infections, some of these
could one day be repurposed for use as radiation medical
countermeasures.
ACKNOWLEDGMENTS
In Memoriam
A friend and colleague of the NIAID, Col. (ret.) and Dr. David Barillo
sadly passed away due to complications from COVID 19 on August 11,
2020. David was an important mentor and voice in the community in the
area of cutaneous radiation injuries (as the Medical Director of Argentum),
due in part to his career devoted to the care of combat casualties, and as a
lead burn surgeon. His great personality, passion for science and
dedication to saving lives will be missed by all who were fortunate
enough to know him.
Received: August 3, 2020; accepted: September 14, 2020; published
online: October 16, 2020
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24 RIOS ET AL.
