JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO.

-, 2020
ª 2020 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

STATE-OF-THE-ART REVIEW

COVID-19 Clinical Trials

A Primer for the Cardiovascular and Cardio-Oncology
Communities

Bonnie Ky, MD, MSCE,a Douglas L. Mann, MDb

HIGHLIGHTS

SARS-CoV-2, the virus that causes COVID-19, is a novel CoV that infects humans by binding to ACE2, which degrades
angiotensin II, and hence plays a critical role in modulating the renin angiotensin system (RAS).

The emerging epidemiology of COVID-19 suggests that patients with cardiovascular risk factors, including older age,
cardiovascular disease, or cancer may be more susceptible to infection and suffer from worse clinical outcomes.

Because of the limited understanding with respect to the interaction of RAS inhibitors and SARS-CoV-2 infectivity, we
endorse current society recommendations to continue RAS antagonists for clinical indications for which these agents are
known to be beneficial.

Treatments for COVID-19 that are undergoing clinical trials range from therapies that block the entry of SARS-CoV-2 into
host cells, to repurposed antiviral therapies such as protease inhibitors and nucleoside analogs that block viral replication
by inhibiting viral RNA-dependent RNA polymerase.

SUMMARY

The coronavirus disease-2019 (COVID-19) pandemic has resulted in a proliferation of clinical trials designed to slow the
spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Many therapeutic agents that are being used
to treat patients with COVID-19 are repurposed treatments for influenza, Ebola, or for malaria that were developed
decades ago and are unlikely to be familiar to the cardiovascular and cardio-oncology communities. Here, the authors
provide a foundation for cardiovascular and cardio-oncology physicians on the front line providing care to patients with
COVID-19, so that they may better understand the emerging cardiovascular epidemiology and the biological rationale for
the clinical trials that are ongoing for the treatment of patients with COVID-19.
(J Am Coll Cardiol Basic Trans Science 2020;-:-–-) © 2020 Published by Elsevier on behalf of the American College of
Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

From the aDepartment of Medicine, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadel-
phia, Pennsylvania; and the bDepartment of Medicine, Division of Cardiology, Center for Cardiovascular Research, Washington
University School of Medicine, St. Louis, Missouri. This work was supported by grants from the National Institutes of Health
(R21HL141802, R34HL146927, and R01HL118018 to Dr. Ky; and R01HL107594 and U10 HL110309 to Dr. Mann) and the American
Heart Association (TPA34910059 to Dr. Ky).
This paper will co-publish in JACC: Basic to Translational Science and JACC: CardioOncology.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ in-
stitutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit
the JACC: Basic to Translational Science author instructions page.

Manuscript received April 13, 2020; accepted April 13, 2020.

ISSN 2452-302X https://doi.org/10.1016/j.jacbts.2020.04.003

2 Ky and Mann JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020
COVID-19 Primer for CV and Cardio-Oncology Communities - 2020:-–-

T
ABBREVIATIONS he coronavirus disease-2019 The median duration of hospitalization was 12.0 days
AND ACRONYMS (COVID-19) pandemic has resulted (IQR: 10.0, 14.0 days); however, the majority of the
in a proliferation of clinical trials patients (93.6%) remained hospitalized at the time of
ACE = angiotensin-converting
enzyme
that are designed to slow the spread of severe data analysis and as such, the clinical course still
acute respiratory syndrome coronavirus -2 largely remains to be defined.
AT1R = angiotensin II type 1
receptor (SARS-CoV-2), the virus that causes COVID- COVID-19 AND CARDIOVASCULAR COMPLICATIONS.
CI = confidence interval 19. These therapies range from vaccines, to Epidemiologic data thus far suggest that patients with
CoV = coronavirus
repurposed treatments for influenza, to cardiovascular risk factors, including older age, car-
drugs that were not effective in patients diovascular disease, or cancer are more susceptible to
COVID-19 = coronavirus
disease-2019 with Ebola, to treatments for malaria that infection and suffer from worse clinical outcomes (4).
FDA = Food and Drug were developed decades ago. Recognizing COVID-19 can also directly result in a number of car-
Administration that patients with underlying cardiovascular diovascular complications, including fulminant
IFN = interferon risk factors, cardiovascular disease, or cancer myocarditis, myocardial injury, heart failure, and
IL = interleukin have an increased risk for adverse outcomes arrhythmia (3,5,6). There have been a number of
IQR = interquartile range with COVID-19, and recognizing that these published case reports of clinically suspected
MERS = Middle East
vulnerable populations may be enrolled in myocarditis as suggested by: markedly elevated
respiratory syndrome COVID-19 clinical trials, here we present a troponin levels, ST-segment elevation on electrocar-
RAS = renin-angiotensin critical review of the rationale for the diogram without obstructive coronary disease,
system different therapeutics that are currently be- severely decreased left ventricular systolic function,
RNA = ribonucleic acid ing employed. As background, we first review and shock (7), with cardiac magnetic resonance im-
sACE2 = soluble angiotensin- the epidemiology of COVID-19, followed by aging evidence of diffuse myocardial edema and
converting enzyme 2 the biology of CoV. We then briefly define gadolinium enhancement (8). However, in another
SARS-CoV-2 = severe acute the complex interplay between the CoV and isolated autopsy report from a patient who suffered
respiratory syndrome
the renin-angiotensin system (RAS), which from SARS-CoV-2–related pneumonia and cardiac ar-
coronavirus-2
is directly relevant to the care of the majority rest, no obvious histological changes in the myocar-
TMPRSS2 = transmembrane
protease serine 2 of patients with cardiovascular disease or dium were observed with the exception of few
cancer who are receiving drugs that modu- interstitial mononuclear inflammatory infiltrates (9).
late this system. Finally, we review the mechanisms Elevated troponin levels have also been observed
of action of the multiple therapies that are currently in those with worse clinical outcomes. In a retro-
being studied in clinical trials. Given the breadth of spective, single-center analysis of 416 hospitalized
information that is emerging, we will not discuss patients with confirmed COVID-19, 19.7% displayed
the role of vaccines. evidence of cardiac injury, as defined by elevated
high-sensitivity troponin I levels greater than the
EPIDEMIOLOGY OF COVID-19
99th percentile upper limit. Those with confirmed
cardiac injury tended to be older (median age of 74 vs.
The current impact of the novel CoV, SARS-CoV-2 is
60 years) and suffer from hypertension (59.8% vs.
unquantifiable. The number of confirmed cases and
23.4%), diabetes (24.4% vs. 12.0%), coronary heart
deaths from the global COVID-19 pandemic increase
disease (29.3% vs. 6.0%), heart failure (14.6% vs.
daily (1,2). Although there is a great deal that still
1.5%), or cancer (8.5% vs. 0.6%) (10).
remains to be understood, initial reports from 552
hospitals in China describing 1,099 of the 7,736 pa- COVID-19 IN PATIENTS WITH CARDIOVASCULAR
tients infected with COVID-19 provide some insight RISK FACTORS OR DISEASE. Patients with cardio-
into the disease (3). In this multicenter retrospective vascular risk factors or disease are at increased risk of
analysis, the majority were Wuhan residents or had suffering from worse clinical outcomes with COVID-
contact with Wuhan residents, although 25.9% were 19. In an analysis of 2 cohorts from Jinyintan Hospi-
neither. The median age of patients was 47 years tal and Wuhan Hospital of 191 patients, patients with
(interquartile range [IQR]: 35 to 58 years), and 41.9% hypertension, diabetes, or coronary heart disease
were female. Patients with more severe disease, were at increased risk of in-hospital mortality (11).
compared with those with nonsevere disease, tended The prevalence of hypertension among nonsurvivors
to be older and tended to suffer from at least 1 co- was 48% as compared to 30% in survivors; 31% versus
morbidity. In this retrospective analysis, patients 19% for diabetes, and 13% versus 8% for cardiovas-
commonly received intravenous antibiotics (58.0%). cular disease. These comorbidities were also more
Oseltamivir was administered in 35.8%, systemic likely to be present in patients who required intensive
steroids in 18.6%, and oxygen in 41.3% of patients. care unit admission (4). Other studies, including a
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020 Ky and Mann 3
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recently published meta-analysis of 46,248 infected Patients with cancer who were recently treated with
patients, have corroborated the observation that pa- chemotherapy or surgery were also more likely to
tients with cardiovascular risk factors or cardiovas- suffer from clinically severe adverse events. Howev-
cular disease have worse clinical outcomes (12) and er, there is a critical need for additional studies to
also suggest that hypertension (17  7%; 95% confi- validate these early observations.
dence interval [CI]: 14% to 22%), diabetes (8  6%;
THE CoV FAMILY
95% CI: 6% to 11%), and cardiovascular disease (5 
4%; 95% CI: 4% to 7%) were prevalent comorbidities
CoVs represent a large family of hundreds of envel-
among infected patients. Recent studies have also
oped, single-stranded, positive-sense ribonucleic
demonstrated that age and hypertension were pre-
acid (RNA) viruses that establish an infection pri-
dictors of an increased likelihood of cardiovascular
marily by targeting the mucosal surfaces of respira-
complications, and cardiovascular complications
tory and intestinal tracts of a wide range of mammals
were associated with a 4.26-fold increased risk of
and birds. There are 4 main subgroupings of CoVs:
death (95% CI: 1.9 to 9.49) (10).
alpha, beta, gamma, and delta (16). The 7 CoVs that
COVID-19 IN PATIENTS WITH HEART TRANS- are capable of infecting humans include 229E (alpha
PLANTATION. There have been case series published CoV), NL63 (alpha CoV), OC43 (beta CoV), HKU1 (beta
on COVID-19 infection in heart transplant recipients. CoV), Middle East respiratory syndrome (MERS)-CoV
Two confirmed cases suggest similar presentations to (beta CoV), SARS-CoV (beta CoV), and SARS-CoV-2
nontransplant recipients and both patients demon- (beta CoV). The prototype human CoV isolates 229E
strated clinical improvement. A questionnaire of 87 and OC43 have been causally linked to the common
heart transplant recipients in China, of which cold. SARS-CoV is the cause of the SARS, whereas
importantly 96.6% undertook quarantine procedures, MERS-CoV was established as the cause of MERS.
did not suggest a markedly elevated rate of SARS- Identification and sequencing of the virus responsible
CoV-2 infection in this population (13,14). for COVID-19 established that it was a novel CoV that
shared 88% sequence identity with 2 bat-derived
COVID-19 IN PATIENTS WITH CANCER. In a retro-
SARS-like CoVs (16). Subsequently, the 2019 novel
spective medical review of 1,524 patients with cancer
CoV was shown to share a 79.5% sequence homology
who were admitted to the Department of Radiation
with SARS-CoV and was subsequently renamed SARS-
and Medical Oncology in Zhongnan Hospital of
CoV-2 (16). The genome of the CoVs encodes 4 major
Wuhan University from December 30, 2019, to
structural proteins: the spike (S) protein, nucleo-
February 17, 2020, the infection rate of SARS-CoV-2 in
capsid protein, membrane protein, and the envelope
patients with cancer was 0.79% (95% CI: 0.3% to 1.2%)
protein (Central Illustration). The S protein is respon-
(15). In contrast, the estimated cumulative incidence
sible for facilitating entry of the CoV into the target
of all COVID-19 cases in Wuhan was 0.37%. As a
cell (16,17) and is composed of a short intracellular
result, the odds of infection in patients with cancer
tail, a transmembrane anchor, and a large ectodomain
were estimated to be 2.31 (95% CI: 1.89 to 3.02)
that consists of a receptor binding S1 subunit and a
greater. Patients with cancer who were infected had a
membrane-fusing S2 subunit (16).
median age of 66 years and were more likely to have
non–small cell lung cancer (58.3%). Five of these pa- CoV VIROLOGY
tients were being treated with chemotherapy,
immunotherapy, or radiation therapy. Three deaths Given that far more is known with respect to the
were recorded. virology of SARS-CoV than of SARS-CoV-2, and given
In a multicenter, prospective cohort study of 2,007 that these 2 CoVs appear to have some overlapping
cases from 575 hospitals, 1% of the 1,590 COVID-19 biology and clinical presentations, we will discuss
cases had a history of cancer (15). This in contrast to these 2 viruses together, with an emphasis on the
an incidence of cancer in the Chinese population of most recent studies that have revealed unique bio-
0.29% per 100,000 people. Again, among those logical aspects of SARS-CoV-2. We will review viral
infected, lung cancer was most common, and patients attachment, entry, and replication of SARS-CoV and
tended to be older. Patients with cancer also suffered SARS-CoV-2 in host cells. This discussion will be in-
from an increased risk of adverse events that tended tegrated with a review of the ongoing clinical trials
to occur earlier, including admission to the intensive that target these different aspects of the biology of
care unit, need for invasive ventilation, or death, SARS-CoV-2 (see Tables 1 to 5).
which occurred in 7 of 18 patients (39%), compared Angiotensin-converting enzyme 2 (ACE2) is the
with 124 of 1,572 patients without cancer (8%). entry receptor for SARS-CoV and SARS-CoV-2. Viruses
4 Ky and Mann JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020
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C E N T R A L IL L U ST R A T I O N SARS-CoV-2 Structure and Entry Into Cells

Ky, B. et al. J Am Coll Cardiol Basic Trans Science. 2020;-(-):-–-.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus genome encodes 4 major structural proteins: the spike (S) protein;
the nucleocapsid (N) protein; the membrane (M) protein; and the envelope (E) protein. The S protein is responsible for facilitating entry of the
CoV into the target cell. The routes employed by SARS-CoV include endocytosis and membrane fusion. The route employed by SARS-CoV-2
is via endocytosis; whether SARS-CoV-2 enters cells by membrane fusion is not known. Binding of the S protein of SARS-CoV to angiotensin-
converting enzyme 2 (ACE2) leads to the uptake of the virions into endosomes, where the viral S protein is activated by the pH-dependent
cysteine protease cathepsin L. Activation of the S protein by cathepsin L can be blocked by bafilomycin A1 and ammonium chloride, which
indirectly inhibit the activity of cathepsin L by interfering with endosomal acidification. Chloroquine and hydroxychloroquine are weak bases
that diffuse into acidic cytoplasmic vesicles such as endosomes, lysosomes, or Golgi vesicles and thereby increases their pH. MDL28170
inhibits calpain and cathepsin L. SARS-CoV can also directly fuse with host cell membranes, after processing of the virus spike protein by
transmembrane protease serine 2 (TMPRSS2), a type II cell membrane serine protease. Camostat mesylate is an orally active serine protease
inhibitor. Modified from Simmons et al. (25). RNA ¼ ribonucleic acid.

enter cells by binding to host cell-encoded proteins activation of the RAS, by processing angiotensin I
that facilitate the entry of the virus into the cell, as (angiotensin 1-10) to angiotensin II (angiotensin 1-8),
well as allow the virus to survive and replicate within the major effector peptide of RAS, which mediates its
the cell. Some viruses, including certain strains of effects through selective interactions with G-protein–
CoVs are capable of down-modulating the entry re- coupled angiotensin II type 1 (AT1) and type 2 (AT2)
ceptor once they gain access to the cell. Receptor receptors (19). ACE, however, has not been implicated
down-modulation is a strategy broadly used by many in the entry of human CoVs into cells.
viruses to escape the immune system, as well as ACE2 is highly expressed in the mouth, tongue,
establish the best environment for viral replication and types I and II alveolar epithelial cells in the lungs.
and spread (18). Receptor down-modulation may also ACE2 is also abundantly expressed by cardiovascular
disrupt many of the natural physiologic functions of endothelium, cardiac myocytes, cardiac fibroblasts,
the host cell, resulting in cell death leading to organ as well as epithelial cells of the kidney and testis. The
level dysfunction. major substrate of ACE2 is angiotensin II, which is
The entry receptor utilized by both SARS-CoV and cleaved to angiotensin 1-7 (Figure 1) and functions
SARS-CoV-2 is ACE2 (Central Illustration), which is a through association with the G-protein–coupled re-
type I transmembrane carboxypeptidase with 40% ceptor Mas receptor. The ACE2–angiotensin (1–7)–Mas
homology to ACE. ACE plays a critical role in receptor axis is regarded as the counter-regulatory
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T A B L E 1 Select Treatment Trials Targeting RAS

Mechanism of Targeted Primary Outcome

Drug Name Action NCT Number Title Study Population Enrollment Study Design Measure

Losartan Anti-RAS NCT04312009 Losartan for Patients Age $18 yrs with presumptive positive laboratory 200 Randomized, double- Difference in
With COVID-19 test for SARS-CoV-2; admission to the hospital blind, placebo oxygenation
Requiring with a sequential organ failure assessment score controlled status at 7 days
Hospitalization $1 and increased oxygen requirement;
randomization within 24 h of presentation
Losartan Anti-RAS NCT04311177 Losartan for Patients Age $18 yrs with presumptive positive laboratory 516 Randomized, double- Hospital admission
With COVID-19 test for SARS-CoV-2 or URI or fever blind, placebo up to 15 days
Not Requiring controlled
Hospitalization

For an up-to-date listing of trials, search for “COVID-19” at the ClinicalTrials.gov website.
COVID-19 ¼ coronavirus disease-2019; NCT ¼ national clinical trial; OFA ¼ organ failure assessment; RAS ¼ renin-angiotensin system; SARS-CoV-2 ¼ severe acute respiratory syndrome coronavirus-2;
URI ¼ upper respiratory infection.

arm of the RAS by opposing the effects of the ACE– that SARS-CoV (23). However, monoclonal antibodies
angiotensin II axis–AT1. Although the precise role of raised against the receptor binding domain of the S1
ACE2 is still being evaluated, studies been shown that protein of SARS-CoV do not bind to the receptor
ACE2 exerts protective effects in the pulmonary and binding domain of the S1 protein of SARS-CoV-2,
the cardiovascular systems, where it serves to oppose suggesting that SARS-directed antibodies are not
the deleterious effects of RAS activation (20–22). cross reactive and that SARS-CoV-2 proteins are
Infection with SARS-CoV and SARS-CoV-2 is trig- necessary to develop effective antibodies. Although
gered by binding of the S protein on the surface of the ACE inhibitors do not inhibit ACE2, Hoffman et al. (23)
CoV to ACE2 that is expressed on the cell surface. The demonstrated that anti-ACE2 antibody prevented
receptor binding domain of the S protein of SARS- entry of viral vectors into cell lines expressing the
CoV-2 is located on the S1 subunit, which undergoes SARS-CoV-2 S protein.
a conformational change when it binds to ACE2,
which facilitates viral attachment to the surface of INTERACTION OF CoV WITH THE RAS. An additional
target cells (17). Binding of SARS-CoV-2 to ACE2 can layer of complexity to understanding the patho-
result in uptake of virions into endosomes (Central physiology of the SARS-CoV-2 in humans stems from
Illustration). Viral entry into the cell requires prim- the complexity of the interactions of CoVs with the
ing of the S protein by the serine protease trans- RAS (Figure 1), as well as the widespread use of drugs
membrane protease serine 2 (TMPRSS2), which that interfere with the RAS, including ACE
cleaves the viral S protein at the S1/S2 and the S2 0 site inhibitors, angiotensin-receptor antagonists, or
and allows fusion of viral and cellular membranes angiotensin receptor-neprilysin inhibitors. Each of
(23). The S proteins of SARS-CoV-2 can also use pH- these drugs has different effects on the expression of
sensitive endosomal proteases (cathepsin B and L) the various components of the RAS in different tissue
for priming and entry into cells. Interestingly, the beds. Here we will briefly discuss these important
binding affinity of the SARS-CoV-2 S ectodomain to interactions, as well as their implications for the
ACE2 is 10- to 20-fold higher than the binding of the treatment of patients with COVID-19.
SARS-CoV ectodomain to ACE2 (17). The increase in Previous studies have shown that SARS-CoV S pro-
stickiness of the SARS-CoV-2 capsid S protein makes teins induce the expression of a cell surface metal-
disease transmission more likely and might explain loenzyme termed a disintegrin and metalloproteinase-
the increased person-to-person transmission with 17, which was originally described as the enzyme that
SARS-CoV-2 compared with that of SARS-CoV. Insofar cleaves membrane-bound tumor necrosis factor-a
as the viral S proteins are the part of the virus that from the cell surface and allows it circulate in the sol-
interacts with the immune system, they may serve as uble form of tumor necrosis factor-a (24). As shown
a promising target for vaccines. Relevant to this dis- in Figure 1, activation of a disintegrin and
cussion, convalescent sera from patients with SARS metalloproteinase-17 results in the proteolytic cleav-
have been shown to block the entry of SARS-CoV-2 age of ACE2 (referred to as shedding) from the cell
entry into cultured cells, albeit with less efficiency surface, with the release of the catalytically active
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T A B L E 2 Select Treatment and Prophylaxis Trials Targeting Viral Cell Entry

Mechanism of Targeted Primary Outcome

Drug Name Action NCT Number Title Study Population Enrollment Study Design Measure

Treatment Trials
Camostat Viral entry NCT04321096 The Impact of Camostat Age 18–110 yrs, COVID-19– 180 Randomized, double- Time to clinical
Mesylate on COVID-19 confirmed hospitalized blind placebo improvement
Infection (CamoCo-19) patients (<48 h) or if controlled, phase at 30 days
hospital-acquired COVID-19 IIa trial
is suspected, <48 h since
onset of symptoms
Hydroxychloroquine Viral entry NCT04315896 Hydroxychloroquine Age 18–80 yrs, COVID-19 500 Randomized, double- All-cause hospital
Treatment for Severe confirmed by RT-PCR in blind, placebo mortality at
COVID-19 Pulmonary any respiratory sample; controlled 120 days
Infection (HYDRA Trial) severe disease defined by
pulse O2< 91%, 3%
decline from baseline
pulse O2, or need for
increased supplemental
O2, mechanical ventilation,
or sepsis
Hydroxychloroquine Viral entry NCT04316377 Norwegian Coronavirus Age >18 yrs, hospitalized, 202 Randomized, Rate of decline in
Disease 2019 Study moderately severe disease open, single arm SARS-CoV viral load
(NO COVID-19) (NEWS score #6); at 96 h
SARS-CoV-2–positive test
Prophylaxis Trials
Chloroquine phosphate Viral entry NCT04303507 Chloroquine/ Age $16 yrs; health care 40,000 Randomized, double- Number of
Hydroxychloroquine worker or front-line blind, placebo symptomatic
Prevention of participant with patient controlled COVID-19
Coronavirus Disease contact working in a infections
(COVID-19) in the health care facility; Severity of
Healthcare Setting inpatient or relative of a symptoms
(COPCOV) patient and likely exposed
to COVID-19; agree to not
self-medicate with
potential antivirals
Hydroxychloroquine Viral entry NCT04308668 Post-exposure Age >18 yrs; exposure to a 3,000 Randomized, double- Incidence of
Prophylaxis/Pre- COVID-19 case within blind, placebo COVID-19
emptive Therapy for 4 days as either a health controlled disease at
SARS-Coronavirus-2 care worker or household 14 days
(COVID-19 PEP) contact; symptomatic Ordinal Scale of
COVID-19 case with COVID-19
confirmed diagnosis within disease severity
4 days of symptom onset; at 14 days
or symptomatic health
care worker with known
COVID-19 contact and
within 4 days of symptom
onset
Hydroxychloroquine Viral entry NCT04318444 Hydroxychloroquine Post Age >18 yrs; household 1,600 Randomized, double- Symptomatic, lab-
Exposure Prophylaxis contact of index case: blind, placebo confirmed
for Coronavirus Disease currently residing in the controlled COVID-19
(COVID-19) same household as an
individual evaluated at
NYP via outpatient, ED, or
inpatient services who (1)
tests positive for COVID-
19, or (2) is defined as
suspected case, or PUI, by
the treating physician
Hydroxychloroquine Viral entry NCT04318015 Hydroxychloroquine Age >18 yrs; health care 400 Randomized, double- Symptomatic
Chemoprophylaxis in personnel exposed to blind, placebo COVID-19
Healthcare Personnel in patients with COVID-19 controlled infection rate
Contact With COVID-19 respiratory disease at 60 days
Patients (PHYDRA (physicians, nurses,
Trial) chemists, pharmacists,
janitors, stretcher-bearer,
administrative, and
respiratory therapists)

For an up-to-date listing of trials, search for “COVID-19” at the ClinicalTrials.gov website.
ED ¼ emergency department; NEWS ¼ National Early Warning Score; NYP ¼ New York Presbyterian; PUI ¼ person under investigation; RT-PCR ¼ reverse transcriptase-polymerase chain reaction; other
abbreviations as in Table 1.
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soluble angiotensin-converting enzyme 2 (sACE2) SARS-CoV-2. Given that we have limited under-
ectodomains into the circulation (22,25). A decrease in standing with respect to the interaction of RAS in-
ACE2 levels on the cell surface would be expected to hibitors, ACE2 levels, and SARS-CoV-2 infectivity in
result in a decrease in the levels of angiotensin 1-7 humans, we do not believe that it is possible to make
(cytoprotective) and a corresponding increase in tissue definitive statements that go beyond the joint state-
levels of angiotensin II (proinflammatory and profi- ment issued on March 17, 2020, by the Heart Failure
brotic). The importance of SARS-CoV2–induced down- Society of America, American College of Cardiology,
regulation of cell surface ACE2 was demonstrated in and American Heart Association, that recommended
experimental studies, wherein administration of re- “continuing renin-angiotensin-aldosterone system
combinant human ACE2 protein, genetic deletion of antagonists for those patients who are currently pre-
the AT1 receptor, or administration of an AT1 receptor scribed such agents for indications for which these
antagonist were shown to be protective in acute lung agents are known to be beneficial” (33).
injury models (21,22). These and other observations ENTRY OF SARS-CoV AND SARS-CoV-2 INTO
have suggested that the use of AT1 receptor antago- CELLS. The entry of enveloped viruses into host cells
nists may be beneficial in patients with COVID-19 (26), occurs through 2 primary mechanisms: the first is
and consistent with this, losartan is currently being direct fusion of the viral membrane with the plasma
tested in randomized, double-blind placebo controlled membrane of the host cells, which allows the virus to
studies as a potential therapy in hospitalized infected directly deliver its genomic material into the cytosol;
patients (Table 1). Relevant to this discussion, the ACE and the second is that the virus hijacks the cell’s
inhibitors in clinical use do not directly affect ACE2 endocytic machinery, by binding to a cell surface
activity (27). The biological significance of circulating receptor, which then triggers endocytosis of the
sACE2 is not known. Of note, sACE2 retains its ability to virus-receptor complex (Central Illustration). In the
bind the S protein of SARS-CoV and was shown to endocytic pathway, the endocytosed virions are
prevent entry of SARS-CoV into cells in vitro (28). subjected to an activation step within the endosome,
Thus, sACE2 may act as a decoy receptor that prevents which is typically mediated by the acidic environ-
SARS-CoV-2 from binding to ACE2 on the cell surface. ment of the endosome, resulting in fusion of the viral
APN01 is a human recombinant sACE2 that has been and endosomal membranes, which allows for the
shown to block the early stages of SARS-CoV-2 in- release of the viral genome into the cytosol. Several
fections in cell culture and human tissue organoid viruses, including human immunodeficiency virus
cultures (29). APN01 has already undergone safety and and SARS-CoV use direct membrane fusions at the
tolerability testing in a phase II trial of healthy volun- cell surface or endocytosis to enter cells. As noted,
teers (NCT00886353), but at the time of this writing is recent studies suggest that SARS-CoV-2 binds to
not being tested clinically in patients with COVID-19. ACE2, which leads to endocytosis of the receptor-
The recognition that many patients with COVID-19 virus complex (23). What is not known at this time
have underlying medical conditions that are treated is whether SARS-CoV-2 is also capable of directly
with ACE inhibitors and AT1 receptor antagonists fusing with the lipid membrane of cells. However,
(30), coupled with the knowledge that higher urinary based on the similarities of how SARS-CoV and SARS-
ACE2 levels have been observed in patients treated CoV-2 behave, it is likely that their modes of entry
with AT1 receptor antagonists (26), has given rise to into cells will be similar. Understanding these dif-
the concern that pharmacologic up-regulation of ferences in cell entry has implications for developing
ACE2 by RAS inhibitors may influence the infectivity novel therapeutics.
of SARS-CoV-2 in a patient population that is already
at high risk for severe COVID-19 infection (31). How- THERAPEUTICS TARGETING ENDOCYTOSIS. The
ever, as noted in a recent review (32) on this topic, the entry of SARS-CoV into cells was shown to occur by
experimental and clinical data often yield conflicting direct fusion of the viral membranes with the plasma
results with respect to the role of ACE inhibitors and membrane of the host cell (Central Illustration),
AT1 receptor antagonists on ACE2 levels in different through a process that requires processing of the viral
pathophysiological contexts. These conflicting results S protein by TMPRSS2 at or near the cell surface.
suggest that the effects on RAS inhibitors on ACE2 are Processing of the S protein exposes the fusion peptide
complex and nuanced and should not be assumed to of the S protein that inserts into the cell membrane,
be the same for all RAS inhibitors, nor should it be which brings the envelope of the viral membrane into
assumed that changes in ACE2 levels in the heart or closer approximation with the membrane of the host
other tissues necessarily reflect changes in ACE2 cell, thereby facilitating fusion (34). At the time of
levels in the lung, which is the portal of entry for this writing, the uptake of SARS-CoV-2 into cells has
8 Ky and Mann JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020
COVID-19 Primer for CV and Cardio-Oncology Communities - 2020:-–-

T A B L E 3 Select Treatment Trials Targeting Viral Replication

Mechanism of
Drug Name Action NCT Number Title

Umifenovir Antiretroviral NCT04260594 Clinical Study of Arbidol Hydrochloride Tablets in the Treatment of
Pneumonia Caused by Novel Coronavirus

ASC09 þ ritonavir; lopinavir þ ritonavir Antiretroviral NCT04261907 Evaluating and Comparing the Safety and Efficiency of ASC09/Ritonavir and
Lopinavir/Ritonavir for Novel Coronavirus Infection

Darunavir þ cobicistat Antiretroviral NCT04252274 Efficacy and Safety of Darunavir and Cobicistat for Treatment of COVID-19
(DC-COVID-19)

Lopinavir þ ritonavir; umifenovir Antiretroviral NCT04252885 The Efficacy of Lopinavir Plus Ritonavir and Arbidol Against Novel
Coronavirus Infection (ELACOI)

Lopinavir þ ritonavir Antiretroviral NCT04330690 Treatments for COVID-19: Canadian Arm of the SOLIDARITY Trial (CATCO)

Remdesivir Antiretroviral NCT04280705 Adaptive COVID-19 Treatment Trial (ACTT)

Remdesivir Antiretroviral NCT04292899 Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734)
in Participants With Severe Coronavirus Disease (COVID-19)

Remdesivir Antiretroviral NCT04292730 Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734)
in Participants With Moderate Coronavirus Disease (COVID-19)
Compared to Standard of Care Treatment

For an up-to-date listing of trials, search for “COVID-19” at the ClinicalTrials.gov website.
ECMO ¼ extracorporeal membrane oxygenation; FiO2 ¼ fraction of inspired O2; nCoV ¼ novel coronavirus; PaO2 ¼ partial arterial O2 pressure; PCR ¼ polymerase chain reaction; RR ¼ respiratory rate; other
abbreviations as in Tables 1 and 2.

been shown to occur through endocytosis of the to increase endosomal pH. Inside cells, chloroquine
SARS-CoV-2–ACE2 complex, which also requires and hydroxychloroquine are rapidly protonated and
priming of the S protein by TMPRSS2. It is not known concentrated in endosomes. The positive charge of
whether SARS-CoV-2 also enters though direct fusion. the chloroquine increases the pH of the endosome,
Based on the evidence linking TMPRSS2-mediated which prevents cathepsin-induced priming of the
SARS-CoV-2 activation to SARS-CoV-2 infectivity viral S protein. Both chloroquine and hydroxy-
(23,35), the small molecule serine protease inhibitor chloroquine decrease SARS-CoV-2 replication in
camostat mesylate may also be an attractive target for cultured cells; however, hydroxychloroquine is more
clinical trials with SARS-CoV-2 (Table 2). Camostat potent than chloroquine (37). In a small single-arm
mesylate has already been shown to inhibit replica- study of patients with confirmed COVID-19, treat-
tion of influenza and parainfluenza viruses and to ment with hydroxychloroquine was associated with a
prevent the development of pneumonia and viral significant difference in clearing of viral nasopha-
myocarditis in infected mice (36). Given that the ryngeal carriage of SARS-CoV-2 within 3 to 6 days
SARS-CoV-2 S protein is activated by the pH- when compared with that of untreated control sub-
dependent cysteine protease cathepsin L, this pro- jects that were studied at 3 to 6 days. Azithromycin
cessing step may be sensitive to inhibition with drugs when added to hydroxychloroquine was significantly
that indirectly inhibit cathepsin L activity by inter- more efficient for virus elimination (38). However,
fering with endosomal acidification (e.g., bafilomycin both therapies can result in QT prolongation, and as
A1) or by compounds that directly block the proteo- such, caution needs to be exercised when using these
lytic activity of cathepsin L. therapies together. Chloroquine and hydroxy-
It has also been suggested that the antimalarial chloroquine can also manifest in cardiotoxicity,
drugs chloroquine and hydroxychloroquine might including cardiomyopathy, both systolic and dia-
exert a potent antiviral effect by virtue of their ability stolic, atrioventricular block, and bundle branch
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020 Ky and Mann 9
- 2020:-–- COVID-19 Primer for CV and Cardio-Oncology Communities

T A B L E 3 Continued

Targeted
Study Population Enrollment Study Design Primary Outcome Measure

Age $18 yrs; subjects with pneumonia diagnosed as 2019-nCoV infection; 380 Randomized, single-arm, open-label Negative viral conversion rate at 7 days
detection of 2019-nCoV nucleic acid–positive by RT-PCR in respiratory umifenovir
tract or blood samples; virus gene sequence of respiratory tract or
blood samples is highly homologous to the known 2019-nCoV
Age between 18 to 75 yrs; lab (RT-PCR) and clinically confirmed case of 160 Randomized, open-label ASC09/ The incidence of adverse outcomes, defined
2019-nCoV pneumonia; hospitalized with a new onset respiratory ritonavir or lopinavir/ritonavir by at least 1 of the following: pulse
illness (#7 days since illness onset) O2 #93% without O2 supplementation,
PaO2-to-FiO2 ratio #300 or RR $30
breaths/min assessed at 14 days
Pneumonia caused by 2019-nCoV 30 Randomized, open-label, The viral clearance rate of throat swabs,
single-arm sputum, or lower respiratory tract
secretions at day 7
Age 18–80 yrs; confirmation of SARS-CoV-2 infection by RT-PCR with 125 Randomized, open-label (1:1:1) to The rate of viral inhibition, as determined by
normal kidney and liver function lopinavir þ ritonavir; or RT-PCR at days 2, 4, 7, 10, 14, and 21
umifenovir; or standard care
Age >6 months with confirmed SARS-CoV-2 by RT-PCR, admitted to 440 Randomized, open-label (1:1) of Efficacy of intervention at 29 days as
hospital lopinavir þ ritonavir or determined by 10-point ordinal scale of
standard care clinical status
Age 18–99 yrs, PCR-confirmed novel coronavirus infection by lab assay; 572 Adaptive, randomized, double-blind Time to recovery at day 29
illness as defined by abnormal radiographic imaging, clinical placebo controlled
assessment, and pulse O2 #94%, requiring O2, or requiring mechanical
ventilation
Age $18 yrs; confirmation of SARS-CoV-2 infection by RT-PCR #4 days 6,000 Randomized, open-label study of Odds of clinical improvement on a 7-point
before randomization; current hospitalization with pulse O2# 94% remdesivir 5 days; or remdesivir ordinal scale by day 11
10 days
Age $18 yrs; confirmation of SARS-CoV-2 infection by RT-PCR #4 days 1,600 Randomized, open-label study of Odds of clinical improvement on a 7-point
before randomization; current hospitalization with fever, pulse remdesivir 5 days; or remdesivir ordinal scale by day 11
O2 >94%, radiographic evidence of pulmonary infiltrates 10 days; or standard of care

block (39). Hydroxychloroquine will be used as one of the SARS-CoV-2 genome, very little is known
the treatment arms in the World Health Organization regarding SARS-CoV-2 replication in cells, let alone
(WHO) multinational SOLIDARITY (Efficacy of how the virus interacts with the host. Given that
Different Antiviral Drugs in SARS-CoV-2) trial (40) antiviral strategies are being considered for treatment
and is also currently being investigated in a number of patients with COVID-19, here we will review what
of other studies (Tables 2 and 5). Interestingly, amio- is generally understood about SARS-CoV replication
darone, which is a cationic amphiphile, was shown to in mammalian cells, recognizing that this information
inhibit Ebola virus infection in vitro in target cells, may change as we learn more about SARS-CoV-2
using concentrations of amiodarone that overlapped (see Figure 2).
those detected in the sera of patients treated for ar- Once the genomic RNA of SARS-CoV is released
rhythmias. Both amiodarone and its main metabolite, into the cytoplasm of the host cell, the positive-
monodesethyl amiodarone, were shown to interfere strand viral RNA is translated on host ribosomes
with the fusion of the viral envelope with the endo- into a large polypeptide termed the replicase, which
somal membrane, thus blocking viral replication (41). undergoes proteolytic cleavage to yield proteins that
Amiodarone has also been shown to inhibit SARS-CoV are required from genome replication, including a
infection and spreading in vitro by altering the late viral RNA-dependent RNA polymerase. The viral
compartments of the endocytic pathway by acting RNA-dependent RNA polymerase generates a full-
after the transit of the virus through endosomes (42). length, antisense negative-strand viral RNA tem-
plate, which is used for replicating positive strand
REPLICATION OF SARS-CoV IN HOST CELLS. viral genomic RNA, as well as shorter subgenomic
Because of the exceptionally large size of the CoV negative strand RNAs that serve as templates for
RNA genome (w30 kb) and the complexity of CoV- synthesizing messenger RNAs that code for structural
host cell interactions, coupled with the novelty of proteins of the virus, including the S, membrane,
10 Ky and Mann JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020
COVID-19 Primer for CV and Cardio-Oncology Communities - 2020:-–-

T A B L E 4 Select Treatment and Prophylaxis Trials Targeting the Immune System

Targeted Primary Outcome

Drug Name Mechanism of Action NCT Number Title Study Population Enrollment Study Design Measure

Treatment Trials
IFN-a1b Immunomodulatory NCT04293887 Efficacy and Safety Age $18 yrs with clinically 328 Randomized, open- Incidence of side
of IFN-a1b in the diagnosed coronavirus label, single-arm effects within
Treatment of Novel pneumonia within 14 days
Coronavirus 7 days, including including
Patients RT-PCR evidence of dyspnea, pulse
coronavirus and O2 #94%, and
symptoms RR $24
breaths/min
Methylprednisolone Immunomodulatory NCT04273321 Efficacy and Safety Age >18 yrs, diagnosis of 400 Randomized, open- Incidence of
of Corticosteroids novel coronavirus label, single-arm treatment
in COVID-19 pneumonia (COVID-19) failure in
14 days
Methylprednisolone Immunomodulatory NCT04244591 Glucocorticoid Therapy Age >18 yrs, RT-PCR– 80 Randomized, open-label Murray lung injury
for COVID-19 confirmed infection, of glucocorticoid score at 7 days
Critically Ill Patients symptoms for >7 days, therapy or standard
With Severe Acute PaO2/FiO2 <200, of care
Respiratory Failure positive pressure
ventilation or HFNC
higher than 45 l/min
for <48 h, requiring ICU
admission
Sarilumab Immunomodulatory NCT04315298 Evaluation of the Age $18 yrs; confirmation 400 Adaptive, randomized, Percent change in
Efficacy and Safety of SARS-CoV-2 infection double-blind, C-reactive
of Sarilumab in by RT-PCR; current placebo-controlled protein levels
Hospitalized hospitalization with with high and low at 4 days
Patients With evidence of pneumonia doses Percentage of
COVID-19 and severe disease, patients
critical disease, or reporting
multiorgan system clinical severity
dysfunction rated on a
7-point ordinal
scale
Siltuximab Immunomodulatory NCT04329650 Efficacy and Safety Age $18 yrs; 100 Randomized, open-label Proportion of
of Siltuximab vs. confirmation of of siltuximab or patients
Corticosteroids in SARS-CoV-2 methylprednisolone requiring ICU
Hospitalized infection by admission at
Patients With RT-PCR; current 29 days
COVID-19 hospitalization with
Pneumonia evidence of pneumonia;
maximum O2 support of
35%
Tocilizumab Immunomodulatory NCT04317092 Tocilizumab in COVID-19 No age or sex limit; 400 Open-label, single-arm Mortality at
Pneumonia SARS-CoV-2 1 month
(TOCIVID-19) infection by
RT-PCR, current
hospitalization
secondary to
pneumonia; pulse
O2 #93%, requiring O2,
or requiring mechanical
ventilation (invasive or
noninvasive)
Continued on the next page

envelope, and nucleocapsid proteins. Translation of and maturation, virions are transported to the cell
viral messenger RNAs occurs using the host endo- surface in vesicles and released by exocytosis (43,44).
plasmic reticulum. Once the viral structural proteins,
S, envelope, and membrane, are translated in the THERAPEUTICS FOR VIRAL REPLICATION. There are

endoplasmic reticulum, they move along the secre- a number of antiviral drugs that are being repurposed
tory pathway to the endoplasmic reticulum-Golgi in- for the treatment of SARS-CoV-2. A partial list of these
termediate compartment. There, the viral proteins antiviral drugs are discussed next.
become encapsulated and bud into membranes con- N u c l e o s i d e a n a l o g s . Remdesivir (GS-5734, Gilead
taining viral structural proteins. Following assembly Sciences, Inc., Foster City, California) is a nucleoside
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020 Ky and Mann 11
- 2020:-–- COVID-19 Primer for CV and Cardio-Oncology Communities

T A B L E 4 Continued

Targeted Primary Outcome

Drug Name Mechanism of Action NCT Number Title Study Population Enrollment Study Design Measure

Tocilizumab Immunomodulatory NCT04320615 A Study to Evaluate Age $18 yrs; hospitalized 330 Randomized, double- Clinical status
the Safety and with COVID-19 blind placebo using a
Efficacy of pneumonia per WHO controlled 7-category
Tocilizumab in criteria; pulse O2 #93% ordinal scale at
Patients With or PaO2/FiO2 <300 28 days
Severe COVID-19
Pneumonia
(COVACTA)
Anakinra, Immunomodulatory NCT04330638 Treatment of COVID-19 Age $18 yrs; hospitalized with 342 Randomized, open-label Time to clinical
siltuximab, Patients With Anti- confirmed COVID-19 (1:1:1:1) to anakinra, improvement at
or tocilizumab interleukin Drugs diagnosis by RT-PCR or or siltuximab, or 15 days
(COV-AID) other laboratory test; anakinra þ siltuximab,
hypoxia defined by PaO2/ or tocilizumab, or
FiO2; CXR or CT scan with anakinra þ tocilizumab
bilateral infiltrates
Prophylaxis Trial
Recombinant human Immunomodulatory NCT04320238 Experimental Trial of Age 18 to 65 yrs, formally 2,944 2-arm, open-label to New COVID-19
IFN-a1b and rhIFNa Nasal Drops serving as medical staff IFN-a1b in a low-risk diagnosis at
thymosin a1 to Prevent 2019- in Taihe Hospital group and IFN-a1b 28 days
nCOV in Medical and thymosin a1 in a
Staff high-risk group

For an up-to-date listing of trials, search for “COVID-19” at the ClinicalTrials.gov website.
CT ¼ computed tomography; CXR ¼ chest x-ray; HFNC ¼ high flow nasal cannula; ICU ¼ intensive care unit; IFN ¼ interferon; rhIFN ¼ recombinant human interferon; WHO ¼ World Health Organization;
other abbreviations as in Tables 1 to 3.

analog that exhibits broad antiviral activity. Remde- Favipiravir (Avigan, Fujifilm Toyama Chemical,
sivir is a prodrug that is metabolized to its active form Tokyo, Japan) is another nucleoside analog antiviral
GS-441524, which interferes with the action of viral drug that inhibits viral RNA-dependent RNA poly-
RNA-dependent RNA polymerase, resulting in a merase. Like remdesivir, it is a prodrug that is
decrease in viral RNA production. It is not known, metabolized to its active form, favipiravir-ribofur-
however, whether remdesivir terminates RNA chains anosyl-5’-triphosphate. Although favipiravir has un-
or causes mutations in them. Remdesivir was effec- dergone phase III clinical trials for the treatment of
tive against multiple types of CoVs in cell culture and influenza, it is not yet approved by the U.S. Food and
a mouse model of SARS (45); however, it did not show Drug Administration (FDA). Japan has granted
an effect in patients with Ebola. Remdesivir is approval for favipiravir for treating viral strains un-
currently being tested in several clinical trials for responsive to current antivirals. In preliminary
hospitalized patients with COVID-19 and pneumonia studies, favipiravir was shown to have more potent
(Tables 3 and 5). Remdesivir is also 1 of the 4 treat- antiviral activity than lopinavir/ritonavir (47).
ment arms in the multinational SOLIDARITY trial, Ribavirin (Copegus, Genentech Inc., San Francisco,
which is the World Health Organization’s sponsored California) is a prodrug that acts as nucleoside in-
multinational randomized, open clinical trial to hibitor. The metabolites of ribavirin resemble aden-
evaluate the safety and comparative efficacy of osine or guanosine nucleosides that then become
hydroxychloroquine, remdesivir, the combination of incorporated into viral RNA and inhibit RNA-
lopinavir and ritonavir, and the combination lopina- dependent replication in RNA viruses. Ribavirin is
vir and ritonavir plus interferon-beta (40). SOLI- currently FDA-approved for the treatment of chronic
DARITY will use an adaptive design, which will allow hepatitis C virus infection in combination with
for discontinuation of drugs that lack effectiveness, peginterferon alfa-2a (Pegasys, Genentech).
as well as adding new drugs that appear promising. P r o t e a s e i n h i b i t o r s . Lopinavir is a protease inhibi-
This type of trial design offers flexibility and effi- tor class that is used in fixed-dose combination with
ciency, particularly in the identification of early sig- another protease inhibitor, ritonavir (lopinavir/rito-
nals related to either efficacy or toxicity, while navir (Kaletra, AbbVie Inc., North Chicago, Illinois))
maintaining study validity (46). for the treatment of human immunodeficiency virus.
12 Ky and Mann JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020
COVID-19 Primer for CV and Cardio-Oncology Communities - 2020:-–-

T A B L E 5 Select Treatment Trials With Multiple Targets

Mechanism
Drug Name of Action NCT Number Title

Lopinavir þ ritonavir; ribavirin; IFN-b1b Antiretroviral and immunomodulatory NCT04276688 Lopinavir/Ritonavir, Ribavirin and IFN-beta Combination
for nCoV Treatment

Lopinavir þ ritonavir; hydroxychloroquine Antiretroviral and viral entry NCT04307693 Comparison of Lopinavir/Ritonavir or Hydroxychloroquine
in Patients With Mild Coronavirus Disease (COVID-19)
Remdesivir þ hydroxychloroquine; Antiretroviral and viral entry NCT04321616 The Efficacy of Different Anti-viral Drugs in COVID-19
remdesivir; hydroxychloroquine Infected Patients

Combinations of oseltamivir, chloroquine, Antiretroviral and viral entry NCT04303299 Various Combination of Protease Inhibitors, Oseltamivir,
darunavir, ritonavir, lopinavir, oseltamivir, Favipiravir, and Hydroxychloroquine for Treatment
favipiravir of COVID19: A Randomized Control Trial (THDMS-
COVID-19)

Favipiravir; chloroquine phosphate Antiretroviral and viral entry NCT04319900 Clinical Trial of Favipiravir Tablets Combined With
Chloroquine Phosphate in the Treatment of Novel
Coronavirus Pneumonia

Remdesivir; lopinavir þ ritonavir; IFN-b1a; Antiretroviral, viral entry, and NCT04315948 Trial of Treatments for COVID-19 in Hospitalized Adults
hydroxychloroquine immunomodulatory (DisCoVeRy)

Favipiravir þ tocilizumab Antiretroviral and immunomodulatory NCT04310228 Favipiravir Combined With Tocilizumab in the Treatment of
Corona Virus Disease 2019

For an up-to-date listing of trials, search for “COVID-19” at the ClinicalTrials.gov website.
IL ¼ interleukin; other abbreviations as in Tables 1 to 4.

Results from a randomized, open-label study of 199 difference: 5.8%; 95% CI: 17.3% to 5.7%), as was
hospitalized adult patients with confirmed SARS- the detectable viral load. However, there were some
CoV-2 infection assigned 1:1 to lopinavir 400 mg– suggestions of potential benefit with lopinavir/rito-
ritonavir 100 mg twice daily for 14 days with stan- navir with a shorter intensive care unit stay (median:
dard of care or standard of care alone were recently 6 days vs. 11 days) and a shorter time to hospital
published (48). All patients had an oxygen saturation discharge (median: 12 days vs. 14 days). As noted, the
of 94% on room air or a ratio of partial pressure of fixed-dose combination of lopinavir/ritonavir is 1
oxygen to the fraction of inspired oxygen <300 treatment arm in the SOLIDARITY trial (Table 3) (40).
mg Hg. The primary endpoint was time to clinical
improvement, where clinical improvement was IMMUNOMODULATORY THERAPIES. Interferons (IFNs)
defined based on an ordinal scale or survival from the are cytokines that activate the innate immune system
hospital. The study was designed for 80% power with in response to viral infection. Type I interferons (IFN-
a 2-sided significance level of a of 0.05 to detect an 8- a/ b) are synthesized by most cell types in the body
day difference in median time to clinical improve- response to a viral infection, whereas type II inter-
ment. Here, the median time to clinical improvement feron (IFN- g) is produced by immune cells following
was 16.0 days (IQR: 13.0 to 17.0 days) in the lopinavir/ antigen stimulation. Both type I and type II IFNs
ritonavir group compared with 16.0 days (IQR: 15.0 to provoke the synthesis of proteins that have antiviral
18.0 days) with standard care. The mortality at and immunomodulatory effects. Recombinant IFN- b
28 days in the treatment group was similar to that has been shown to inhibit SARS-CoV replication
observed in the standard care group (19.2% vs. 25%; in vitro more effectively than either IFN- a or IFN-g
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020 Ky and Mann 13
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T A B L E 5 Continued

Targeted
Study Population Enrollment Study Design Primary Outcome Measure

Age $18 yrs hospitalized for virologically 127 Randomized, open-label (1:1:1) to lopinavir þ Time to negative nasopharyngeal viral RT-PCR
confirmed 2019-nCoV infection with NEWS $1 ritonavir; or ribavirin; or IFN-b1b assessed up to 1 month
on recruitment; febrile with symptoms and
duration of symptoms #10 days
Age 16–99 yrs with confirmed mild COVID-19 150 Randomized, open-label (1:1:1) lopinavir þ ritonavir; Viral load at hospital days 3, 5, 7, 10, 14, 18
(NEWS 0–4) or hydroxychloroquine; or standard care
Age $18 yrs with confirmed SARS-CoV-2 by 700 Randomized, Open-Label (1:1:1) remdesivir; or In-hospital mortality at 3 weeks
RT-PCR, admitted to hospital or ICU hydroxychloroquine; or remdesivir þ
hydroxychloroquine adaptive controlled design;
comparison with standard of care
Age 16–100 yrs with COVID-19 diagnosis 320 Randomized, open-label, oseltamivir þ chloroquine; Time to negative detection of SARS-CoV-2 in
or darunavir þ ritonavir þ oseltamivir; or nasopharyngeal swab at 24 weeks
lopinavir þ ritonavir þ oseltamivir; or
favipiravir þ lopinavir þ ritonavir; or darunavir þ
ritonavir þ oseltamivir þ chloroquine; or
darunavir þ ritonavir þ favipiravir þ chloroquine
Age 18–75 yrs; diagnosed with nCoV pneumonia 150 Randomized, double-blind 3-arm study of Time to improvement of respiratory symptoms
with a course of illness no more than 14 days; favipiravir þ chloroquine; or favipiravir; or Number of days of viral shedding
if the course is >14 days, no progression by placebo Frequency of improvement of respiratory
chest radiograph within 7 days; respiratory symptoms
symptoms; positive COVID-19 RT-PCR within
3 days
Age $18 yrs, laboratory-confirmed SARS-CoV-2 3,100 Adaptive, randomized, open-label 1:1:1:1:1 to Percentage of subjects reporting disease severity
infection as determined by RT-PCR or other remdesivir; or lopinavir/ritonavir; or lopinavir/ on a 7-point ordinal clinical scale reflective of
assay <72 h prior to randomization, ritonavir þ INF-b1a; or hydroxychloroquine; or hospitalization and oxygenation status; or
hospitalized patients with illness of any standard of care death at 15 days
duration, and pulmonary exam abnormalities
and pulse O2 # 94%, requiring O2, or
requiring mechanical ventilation, or acute
respiratory failure requiring mechanical
ventilation and/or supplemental O2
Age 18–65 yrs, COVID-19 diagnosis, 150 Randomized, open-label (1:1:1) of favipiravir þ Clinical cure rate at 3 months
increased IL-6 tocilizumab; or favipiravir; or tocilizumab

(49,50). Interestingly, IFN-g down-regulates the treatment of severe cytokine release syndrome in
expression of ACE2 on the cell surface and protects patients treated with chimeric antigen receptor T-cell
type I pneumocytes from SARS-CoV infection (51). therapy and is also approved for the treatment of
The combination of lopinavir/ritonavir and IFN-b 1b is rheumatoid arthritis (55–58). Tocilizumab is a mono-
being evaluated in the treatment of laboratory- clonal antibody that binds the IL-6 receptor, both the
confirmed MERS requiring hospitalization (52) and membrane-bound and soluble forms, thus inhibiting
will also be evaluated in the SOLIDARITY trial (40). both classic and trans-IL-6 downstream signaling.
A number of additional immunomodulatory agents Similarly, the IL-6 humanized murine chimeric
are also currently being evaluated, including the monoclonal antibody siltuximab, although not FDA-
interleukin (IL)-6 inhibitor, tocilizumab, and gluco- approved for the treatment of cytokine release syn-
corticosteroids (Tables 4 and 5), given the cytokine drome, has also been used in the treatment of cyto-
storm syndrome that has been observed in subgroups kine release syndrome and is also being studied as a
with severe COVID-19 (53) with increased levels of potential therapy in severe COVID-19 infections. Sil-
IL-2, IL-6, IL-7, and additional inflammatory cyto- tuximab (Sylvant, Janssen Biotech Inc., Horsham,
kines (54). One meta-analysis suggested that the Pennsylvania) binds directly to IL-6 and prevents the
mean IL-6 levels were 2.9-fold (95% CI: 1.17 to 7.19- activation of immune effector cells. Sarilumab (Kev-
fold) greater in patients with complicated compared zara, Sanofi US, Bridgewater, New Jersey) is a human
with noncomplicated COVID-19 (54). Tocilizumab monoclonal antibody against the IL-6 receptor that
(Actemra, Genentech) is FDA-approved for the was developed for the treatment of rheumatoid
14 Ky and Mann JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020
COVID-19 Primer for CV and Cardio-Oncology Communities - 2020:-–-

F I G U R E 1 Interaction of CoVs With the RAS

Angiotensin-converting enzyme (ACE) converts angiotensin I (ANG1) (angiotensin 1-10) to angiotensin II (ANG2) (angiotensin 1-8), which is
the major effector peptide of the renin-angiotensin system (RAS). ANG2 mediates its effects through selective interactions with G-protein–
coupled angiotensin II type 1 receptor (AT1R) and G-protein–coupled angiotensin II type 1 type 2 receptor (AT2R). ANG2 is degraded to
ANG-(1-7) by angiotensin-converting enzyme 2 (ACE2), ANG-(1-7) binds to the Mas receptor (not shown). The ACE2–ANG-(1-7)–Mas receptor
axis opposes the effects of ACE–ANG2–AT1 axis. The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike
protein to ACE2 induces ACE2 shedding by activating a disintegrin and metalloproteinase-17 (ADAM-17). A decrease in ACE2 levels would be
expected to result in a decrease in the levels ANG-(1-7) levels (cytoprotective) and a corresponding increase in tissue levels of ANG2
(proinflammatory and profibrotic). Transmembrane serine protease 2 (TMPRSS2), a type II cell membrane serine protease that activates the
spike protein of SARS-CoV-2 and allows it to bind to ACE2. Modified from Simmons et al. (25). CoVs ¼ coronaviruses; P ¼ phosphorylation.

arthritis that is also being evaluated for severe care providers. Given that the vast majority of pa-
COVID-19. tients with cardiovascular disease are at high risk
There are no systematically obtained clinical data for SARS-CoV-2 infection, the cardiovascular and
yet that support a benefit to the use of steroids, and cardio-oncology communities will play a major
some reports have suggested a possible detriment role in caring for patients with COVID-19 now and for
with delayed viral clearance and increased risk of the foreseeable future. As a community, we have a
infection with MERS and SARS, although the role of long tradition of enrolling patients into clinical
steroids in COVID-19 is an area of active investigation trials that evaluate therapeutic agents whose
(Table 4) (59). mechanisms of action are familiar, which facilitates
reaching clinical equipoise when enrolling patients
COVID-19 AND CARDIOVASCULAR DISEASE in clinical trials. In the coming months, our com-
munities will be asked to contribute patients to
The COVID-19 pandemic has presented innumerable clinical trials where the mechanisms of action of the
challenges to health care organizations and health therapeutic agents are less familiar and the
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F I G U R E 2 The Replication Strategy of SARS-CoV

(a) The severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) glycoprotein attaches to the angiotensin-converting enzyme 2
(ACE2) receptor on the cell surface. On entering the cytoplasm, the viral core particle, which contains the positive (50 to 30 ) strand genomic
ribonucleic acid (RNA), is released into the cytoplasm of the cell (b). The positive-strand viral RNA is translated on host ribosomes to generate
a large polyprotein (c) that undergoes proteolytic processing to generate multiple viral proteins, including an RNA-dependent RNA poly-
merase (RdRp). The RNA-dependent RNA polymerase generates a full-length, antisense negative-strand (30 to 50 ) viral RNA strand (d) that
serves as template for replicating positive-strand viral genomic RNA, as well as shorter negative-strand RNAs (e) that serve as templates for
synthesizing messenger ribonucleic acids (mRNAs) that code for structural proteins of the virus (f), including the S, membrane (M), envelope
(E), and nucleocapsid (N) proteins. Translation of viral mRNAs occurs using the host endoplasmic reticulum (ER) (g). Once the viral structural
proteins, S, E, and M, are translated and inserted into the ER, they move along the secretory pathway to the endoplasmic reticulum-Golgi
intermediate compartment (ERGIC) (h). The viral proteins become encapsulated and bud into membranes containing viral structural proteins,
where mature virions are assembled. (i) Following assembly, virions are transported to the cell surface in vesicles and released by exocytosis.
Modified from Turner et al. (43). ORF ¼ open reading frame.

knowledge base required for providing care for understand the emerging cardiovascular epidemi-
COVID-19 is accelerating at a dizzying pace. Here we ology of COVID-19, as well as the biological
have tried to provide a foundation for physicians rationale for the plethora of clinical trials that are
who are on the front line of providing care to pa- either being designed or are currently recruiting
tients with COVID-19, so that they can better patients.
16 Ky and Mann JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020
COVID-19 Primer for CV and Cardio-Oncology Communities - 2020:-–-

ACKNOWLEDGMENT The authors would like to Center for Translational Research, 3400 Civic Center
acknowledge Elizabeth Thompson for her Boulevard, 11-105, Philadelphia, Pennsylvania 19104.
assistance in reviewing the ClinicalTrials.gov E-mail: [email protected]. OR Dr.
website. Douglas L. Mann, Center for Cardiovascular Research,
Washington University School of Medicine, 660 S. Euclid
ADDRESS FOR CORRESPONDENCE: Dr. Bonnie Ky, Avenue, Campus PO Box 8086, St. Louis, Missouri 63110.
University of Pennsylvania School of Medicine, Smilow E-mail: [email protected].

REFERENCES

1. STAT. The Covid-19 Tracker. Available at: 13. Chen CY, Chen SF, Hollander SA, et al. Donor 27. Rice GI, Thomas DA, Grant PJ, Turner AJ,
https://www.statnews.com/2020/03/26/covid-19- heart selection during the COVID-19 pandemic: a Hooper NM. Evaluation of angiotensin-converting
tracker/. Accessed April 14, 2020. case study. J Heart Lung Transplant 2020;39: enzyme (ACE), its homologue ACE2 and neprily-
498–9. sin in angiotensin peptide metabolism. Biochem J
2. John Hopkins University of Medicine Coronavi-
2004;383:45–51.
rus Resource Center. COVID-19 Dashboard by the 14. Woolley AE, Mehra MR. Dilemma of organ
Center for Systems Science and Engineering donation in transplantation and the COVID-19 28. Jia HP, Look DC, Tan P, et al. Ectodomain
(CSSE) at Johns Hopkins University. Available at: pandemic. J Heart Lung Transplant 2020;39: shedding of angiotensin converting enzyme 2 in
https://coronavirus.jhu.edu/map.html. Accessed 410–1. human airway epithelia. Am J Physiol Lung Cell
April 14, 2020. Mol Physiol 2009;297:L84–96.
15. Liang W, Guan W, Chen R, et al. Cancer pa-
3. Guan WJ, Ni ZY, Hu Y, et al., for the China tients in SARS-CoV-2 infection: a nationwide 29. Monteil V, Kwon H, Prado P, et al. Inhibition of
Medical Treatment Expert Group for COVID-19. analysis in China. Lancet Oncol 2020;21:335–7. SARS-CoV-2 infections in engineered human tis-
Clinical characteristics of coronavirus disease 2019 sues using clinical grade human ACE2. Cell 2020
16. Chen Y, Liu Q, Guo D. Emerging coronaviruses:
in China. N Engl J Med 2020 Feb 28 [E-pub ahead Apr 2 [E-pub ahead of print].
genome structure, replication, and pathogenesis.
of print]. J Med Virol 2020;92:418–23. 30. Yang X, Yu Y, Xu J, et al. Clinical course and
4. Li B, Yang J, Zhao F, et al. Prevalence and outcomes of critically ill patients with SARS-CoV-2
17. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM
impact of cardiovascular metabolic diseases on pneumonia in Wuhan, China: a single-centered,
structure of the 2019-nCoV spike in the prefusion
COVID-19 in China. Clin Res Cardiol 2020 Mar 11 retrospective, observational study. Lancet Respir
conformation. Science 2020;367:1260–3.
[E-pub ahead of print]. Med 2020 Feb 24 [E-pub ahead of print].
18. Landi A, Iannucci V, Nuffel AV, Meuwissen P,
5. Ganatra S, Hammond SP, Nohria A. The novel Verhasselt B. One protein to rule them all: mod- 31. Fang L, Karakiulakis G, Roth M. Are patients
coronavirus disease (COVID-19) threat for patients ulation of cell surface receptors and molecules by with hypertension and diabetes mellitus at
with cardiovascular disease and cancer. J Am Coll HIV Nef. Curr HIV Res 2011;9:496–504. increased risk for COVID-19 infection? Lancet
Cardiol CardioOnc 2020 Mar 20 [E-pub ahead of Respir Med 2020;8:e21.
19. Hartupee J, Mann DL. Neurohormonal activa-
print]. 32. Vaduganathan M, Vardeny O, Michel T,
tion in heart failure with reduced ejection fraction.
6. Libby P. The heart in COVID19: primary target Nat Rev Cardiol 2017;14:30–8. McMurray JJV, Pfeffer MA, Solomon SD. Renin-
or secondary bystander? J Am Coll Cardiol Basic angiotensin-aldosterone system inhibitors in pa-
20. Harding SE, Vescovo G, Jones SM, Gurden J, tients with Covid-19. N Engl J Med 2020 Mar 30
Trans Science 2020 Apr 10 [E-pub ahead of print].
Poole-Wilson PA. Contractile responses of isolated [E-pub ahead of print].
7. Hu H, Ma F, Wei X, Fang Y. Coronavirus fulmi- adult rat and rabbit cardiac myocytes to isopro-
nant myocarditis saved with glucocorticoid and terenol and calcium. J Mol Cell Cardiol 1988;20: 33. Bozkurt B, Kovacs R, Harrington B. HFSA/ACC/
human immunoglobulin. Eur Heart J 2020 Mar 16 635–47. AHA Statement Addresses concerns Re: Using
RAAS Antagonists in COVID-19. Latest in
[E-pub ahead of print].
21. Imai Y, Kuba K, Rao S, et al. Angiotensin-con- Cardiology [ACC news story] March 17, 2020.
8. Inciardi RM, Lupi L, Zaccone G, et al. Cardiac verting enzyme 2 protects from severe acute lung Available at: https://www.acc.org/latest-in-
involvement in a patient with coronavirus disease failure. Nature 2005;436:112–6. cardiology/articles/2020/03/17/08/59/hfsa-acc-
2019 (COVID-19). JAMA Cardiol 2020 Mar 27 [E- 22. Kuba K, Imai Y, Rao S, et al. A crucial role of aha-statement-addresses-concerns-re-using-raas-
pub ahead of print]. angiotensin converting enzyme 2 (ACE2) in SARS antagonists-in-covid-19. Accessed April 14, 2020.
9. Xu Z, Shi L, Wang Y, et al. Pathological findings coronavirus-induced lung injury. Nat Med 2005;11:
34. Cohen FS. How viruses invade cells. Biophys J
of COVID-19 associated with acute respiratory 875–9.
2016;110:1028–32.
distress syndrome. Lancet Respir Med 2020;8: 23. Hoffmann M, Kleine-Weber H, Schroeder S,
35. Kawase M, Shirato K, van der Hoek L,
420–2. et al. SARS-CoV-2 cell entry depends on ACE2 and
Taguchi F, Matsuyama S. Simultaneous treatment
10. Shi S, Qin M, Shen B, et al. Association of TMPRSS2 and is blocked by a clinically proven
of human bronchial epithelial cells with serine and
cardiac injury with mortality in hospitalized pa- protease inhibitor. Cell 2020 Mar 4 [E-pub ahead
cysteine protease inhibitors prevents severe acute
tients with COVID-19 in Wuhan, China. JAMA of print].
respiratory syndrome coronavirus entry. J Virol
Cardiol 2020 Mar 25 [E-pub ahead of print]. 24. Gooz M. ADAM-17: the enzyme that does it all. 2012;86:6537–45.

11. Zhou F, Yu T, Du R, et al. Clinical course and Crit Rev Biochem Mol Biol 2010;45:146–69.
36. Zhirnov OP, Klenk HD, Wright PF. Aprotinin
risk factors for mortality of adult inpatients with 25. Simmons G, Zmora P, Gierer S, Heurich A, and similar protease inhibitors as drugs against
COVID-19 in Wuhan, China: a retrospective cohort Pohlmann S. Proteolytic activation of the SARS- influenza. Antiviral Res 2011;92:27–36.
study. Lancet 2020;395:1054–62. coronavirus spike protein: cutting enzymes at the
37. Yao X, Ye F, Zhang M, et al. In vitro antiviral
cutting edge of antiviral research. Antiviral Res
12. Yang J, Zheng Y, Gou X, et al. Prevalence of activity and projection of optimized dosing design
2013;100:605–14.
comorbidities in the novel Wuhan coronavirus of hydroxychloroquine for the treatment of severe
(COVID-19) infection: a systematic review and 26. Gurwitz D. Angiotensin receptor blockers as acute respiratory syndrome coronavirus 2 (SARS-
meta-analysis. Int J Infect Dis 2020 Mar 12 [E-pub tentative SARS-CoV-2 therapeutics. Drug Dev Res CoV-2). Clin Infect Dis 2020 Mar 9 [E-pub ahead
ahead of print]. 2020 Mar 4 [E-pub ahead of print]. of print].
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2020 Ky and Mann 17
- 2020:-–- COVID-19 Primer for CV and Cardio-Oncology Communities

38. Gautret P, Lagier JC, Parola P, et al. Hydrox- 46. Chow SC. Adaptive clinical trial design. Annu Available at: https://www.medrxiv.org/content/1
ychloroquine and azithromycin as a treatment of Rev Med 2014;65:405–15. 0.1101/2020.03.30.20048058v1. Accessed
COVID-19: results of an open-label non-random- April 3, 2020.
47. Dong L, Hu S, Gao J. Discovering drugs to treat
ized clinical trial. Int J Antimicrob Agents 2020
coronavirus disease 2019 (COVID-19). Drug Discov 55. Neelapu SS, Tummala S, Kebriaei P, et al.
Mar 20 [E-pub ahead of print].
Ther 2020;14:58–60. Chimeric antigen receptor T-cell therapy—assess-
39. Page RL 2nd, O’Bryant CL, Cheng D, et al. ment and management of toxicities. Nat Rev Clin
48. Cao B, Wang Y, Wen D, et al. A trial of
Drugs that may cause or exacerbate heart failure: a Oncol 2018;15:47–62.
lopinavir-ritonavir in adults hospitalized with se-
scientific statement from the American Heart As-
vere Covid-19. N Engl J Med 2020 Mar 18 [E-pub 56. Ghosh AK, Chen DH, Guha A, Mackenzie S,
sociation. Circulation 2016;134:e32–69.
ahead of print]. Walker JM, Roddie C. CAR T cell therapy–related
40. Kuperschmidt K, Cohen J. WHO launches a cardiovascular outcomes and management: sys-
49. Cinatl J, Morgenstern B, Bauer G, Chandra P,
global megatrial of the four most promising temic disease or direct cardiotoxicity? J Am Coll
Rabenau H, Doerr HW. Treatment of SARS with
coronavirus treatments. March 22, 2020. Available Cardiol CardioOnc 2020;2:97–109.
human interferons. Lancet 2003;362:293–4.
at: https://www.sciencemag.org/news/2020/03/
57. Riegler LL, Jones GP, Lee DW. Current ap-
who-launches-global-megatrial-four-most-promising- 50. Spiegel M, Pichlmair A, Muhlberger E, Haller O, proaches in the grading and management of
coronavirus-treatments. Accessed April 14, 2020. Weber F. The antiviral effect of interferon-beta cytokine release syndrome after chimeric antigen
41. Salata C, Baritussio A, Munegato D, et al. against SARS-coronavirus is not mediated by MxA receptor T-cell therapy. Ther Clin Risk Manag
Amiodarone and metabolite MDEA inhibit Ebola protein. J Clin Virol 2004;30:211–3. 2019;15:323–35.
virus infection by interfering with the viral entry 51. Haagmans BL, Kuiken T, Martina BE, et al. 58. Mahmoudjafari Z, Hawks KG, Hsieh AA,
process. Pathog Dis 2015;73:ftv032. Pegylated interferon-alpha protects type 1 pneu- Plesca D, Gatwood KS, Culos KA. American Society
42. Stadler K, Ha HR, Ciminale V, et al. Amiodar- mocytes against SARS coronavirus infection in for Blood and Marrow Transplantation Pharmacy
one alters late endosomes and inhibits SARS macaques. Nat Med 2004;10:290–3. Special Interest Group survey on chimeric antigen
coronavirus infection at a post-endosomal level. 52. Arabi YM, Alothman A, Balkhy HH, et al., for receptor T cell therapy administrative, logistic,
Am J Respir Cell Mol Biol 2008;39:142–9. the MIRACLE Trial Group. Treatment of Middle and toxicity management practices in the United
East respiratory syndrome with a combination of States. Biol Blood Marrow Transplant 2019;25:
43. Turner AJ, Hiscox JA, Hooper NM. ACE2: from
lopinavir-ritonavir and interferon-beta1b (MIRA- 26–33.
vasopeptidase to SARS virus receptor. Trends
Pharmacol Sci 2004;25:291–4. CLE trial): study protocol for a randomized 59. Russell CD, Millar JE, Baillie JK. Clinical evi-
controlled trial. Trials 2018;19:81. dence does not support corticosteroid treatment
44. Fehr AR, Perlman S. Coronaviruses: an over-
53. Mehta P, McAuley DF, Brown M, et al., for the for 2019-nCoV lung injury. Lancet 2020;395:
view of their replication and pathogenesis.
UK HLH Across Specialty Collaboration. COVID-19: 473–5.
Methods Mol Biol 2015;1282:1–23.
consider cytokine storm syndromes and immuno-
45. Sheahan TP, Sims AC, Graham RL, et al. Broad-
suppression. Lancet 2020;395:1033–4.
spectrum antiviral GS-5734 inhibits both epidemic
and zoonotic coronaviruses. Sci Transl Med 2017; 54. Coomes EA, Haghbayan H. Interleukin-6 in KEY WORDS ACE2, clinical trials, COVID-19,
9:eaaal3653. COVID-9: a systematic review and meta-analysis. renin angiotensin system, SARS-CoV-2