Current Approaches to COVID-19: Therapy and Prevention

Abstract

The coronavirus disease-2019 (COVID-19) pandemic has affected millions of people worldwide. As our understanding of the disease is evolving, our approach to the patient management is also changing swiftly. Available new evidence is helping us take radical decisions in COVID-19 management. We searched for inclusion of the published literature on treatment of COVID-19 from around the globe. All relevant evidences available till the time of submission of this article were briefly discussed. Once advised as blanket therapy for all patients, recent reports of hydroxychloroquine with or without azithromycin indicated no potential benefit and use of such combination may increase the risk of arrhythmias. Clinical evidence with newer antivirals such as remdesivir and favipiravir is promising that can hasten the patient recovery and reduce the mortality. With steroids, evidence is much clear in that it should be used in low dose and for short period not extending beyond 7 days in moderate to severe hospitalized patients. Low-molecular-weight heparin should be initiated in all hospitalized COVID-19 patients and dose should be based on the coagulation profile and risk of thromboembolism. Immunomodulatory drugs such tocilizumab may be considered for severe and critically ill patients to improve the outcomes. Though ulinastatin can be a potential alternative immunomodulator, there is lack of clinical evidence on its usage in COVID-19. Convalescent plasma therapy can be potentially lifesaving in critically ill patients. However, there is need to generate further evidence with various such therapies. Though availability of a potent vaccine is awaited, current treatment of COVID-19 is based on available therapies, which is guided by the evidence. In this review, we discuss the potential treatments available around the globe with current evidence on each of such treatments. How to cite this article: Dixit SB, Zirpe KG, Kulkarni AP, Chaudhry D, Govil D, Mehta Y, et al. Current Approaches to COVID-19: Therapy and Prevention. Indian J Crit Care Med 2020;24(9):838-846.

Full text

REVIEW ARTICLE
Current Approaches to COVID-19: Therapy and Prevention
Subhal B Dixit1, Kapil G Zirpe2, Atul P Kulkarni3, Dhruva Chaudhry4, Deepak Govil5, Yan Mehta6, Sameer A Jog7,
Khalid I Khab8, Rahul A Pandit9, Srinivas Samavedam10, Pradeep Rangappa11, Susruta Bandopadhyay12, Om Shrivastav13,
Ujwala Mhatre14
AbstrAct
The COVID-19 pandemic has aected millions of people worldwide. As our understanding of the disease is evolving, our approach to the patient
management is also changing swiftly. Available new evidence is helping us take radical decisions in COVID-19 management. We searched for
inclusion of the published literature on treatment of COVID-19 from around the globe. All relevant evidences available till the time of submission
of this article were briey discussed. Once advised as blanket therapy for all patients, recent reports of hydroxychloroquine with or without
azithromycin indicated no potential benet and use of such combination may increase the risk of arrhythmias. Clinical evidence with newer
antivirals such as remdesivir and favipiravir is promising that can hasten the patient recovery and reduce the mortality. With steroids, evidence is
much clear in that it should be used in low dose and for short period not extending beyond 7 days in moderate to severe hospitalized patients.
Low-molecular-weight heparin should be initiated in all hospitalized COVID-19 patients and dose should be based on the coagulation prole
and risk of thromboembolism. Immunomodulatory drugs such tocilizumab may be considered for severe and critically ill patients to improve
the outcomes. Though ulinastatin can be a potential alternative immunomodulator, there is lack of clinical evidence on its usage in COVID-19.
Convalescent plasma therapy can be potentially lifesaving in critically ill patients. However, there is need to generate further evidence with
various such therapies. Though availability of a potent vaccine is awaited, current treatment of COVID-19 is based on available therapies, which
is guided by the evidence. In this review, we discuss the potential treatments available around the globe with current evidence on each of
such treatments.
Keywords: Coronavirus, Coronavirus disease 2019, Heparin, Hydroxychloroquine, Remdesvir, SARS COV2, Tocilizumab.
Indian Journal of Critical Care Medicine (2020): 10.5005/jp-journals-10071-23470
IntroductIon
The COVID-19 pandemic caused by the SARS-CoV-2 virus has
aected 7,410,510 people globally and caused 418,294 deaths,
so far. The majority of patients of COVID-19 develop only mild
or moderate illness; however, 5% require organ support in the
intensive care unit (ICU).1,2 The case fatality rate (CFR) varies in
dierent countries. The estimated CFR from some of the majorly
aected countries diers substantially from 14.27 in Italy, 14.25 in
the United Kingdom (UK), 11.18 in Spain to 5.6 in the United States,
5.48 in China, 4.71 in Germany, and 2.85 in India.1 The SARS-CoV-2
virus appears to cause immune dysregulation leading to cytokine
storm and progressively wor sening organ damage in patients who
are severely aected. 3 So far, there is no eec tive therapy, and most
healthcare systems have been left to rely on social distancing,
hand hygiene, and personal protection for the general population
and barrier precautions for healthcare workers (HCWs). Therefore,
there is an urgent need to identify therapeutic and preventive
options for COVID-19. Considering the complexity of the disease,
researchers have tried to approach the management of COVID-19,
targeting multiple plausible mechanisms of this highly conta gious
disease. These involve trialing out antivir al, anti-inammatory, and
immunomodulatory th erapies. In this review, we discuss the current
status of investigational drugs and vaccines being developed for
COVID-19. We believe this will enable clinicians to make an informed
decision and optimize the patient outcomes.
current optIons beIng tr I e d f o r
coVId-19 treAtment
Therapeutic options management of COVID-19 can be broadly
categorized into antiviral agents, drugs repurposed as antiviral
drugs, immunomodulators, and adjunctive treatments (Table 1).
© The Author(s). 2020 Open Access This article is distributed unde r the terms of the Creative Commons Attributio n 4.0 International License (https: //creativecommons.
org/licenses/by- nc/4.0/), which permits unrestric ted use, distribution, and non -commercial reproduc tion in any medium, provided yo u give appropriate credit to
the original author(s) and the source, prov ide a link to the Creative Commons license, and indicate if ch anges were made. The Creative Commons Pub lic Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
1Sanjeevan and MJM Hospital, Pune, Maharashtra, India
2Neuro Trauma Unit, Grant Medical Foundation, Pune, Maharashtra,
India
3Division of Critical Care Medicine, Department of Anesthesia, Critical
Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute,
Mumbai, Maharashtra, India
4Department of Pulmonary and Critical Care, Pandit Bhagwat Dayal
Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana,
India
5Institute of Critical Care and Anesthesia, Medanta the Medicty,
Gurgaon, Haryana, India
6Department of Critical Care and Anesthesiology, Medanta the
Medicity, Gurgaon, Haryana, India
7Department of Critical Care and Emergency Medicine, Deenanath
Mangeshkar Hospital, Pune, Maharashtra, India
8Department of Medicine, SKN Medical College, Pune, Maharashtra,
India
9Intensive Care Unit, Fortis Hospital, Mumbai, Maharashtra, India
10Department of Critical Care, Virinchi Hospital, Hyderabad, Telangana,
India
11Columbia Asia Hospital, Bengaluru, Karnataka, India
12Department of Critical Care, AMRI Hospital, Salt Lake, Kolkata, West
Bengal, India
13Jaslok Hospital, Mumbai, Maharashtra, India
14Department of Critical Care, Nanavati Hospital, Mumbai, Maharashtra,
India
Corresponding Author: Subhal B Dixit, Sanjeevan and MJM
Hospital, Pune, Maharashtra, India, Phone: +91 9822050240, e-mail:
subhaldixit@yahoo.com
How to cite this article: Dixit SB, Zirpe KG, Kulkarni AP,
Chaudhry D, Govil D, Mehta Y, et al. Current Approaches to

Current Approaches to COVID-19: erapy and Prevention
Indian Journal of Crical Care Medicine, Volume 24 Issue 9 (September 2020) 839
Antiviral Drugs
As the majority of patients with COVID-19 have a mild infection,
there may not be a need for any specic antiviral therapy in most
patients. However, our experience with influenza and severe
acute respiratory syndrome (SARS) infections indicates that early
institution of the antiviral therapy may shorten the course of
disease. Though there is a pressing need to nd an antiviral drug
from randomized clinic al trials (RCTs), most of these agents are us ed
based on in vitro and extrapolated data.4
Remdesivir
Remdesivir is a nucleoside analog prodrug. In vitro studies have
demonstrated its inhib itory eect on pathoge nic animal and human
coronaviruses including SARS-CoV-2.5
A study from Grein et al. tried using remedesivir in 61
patients with severe COVID-19, for a 10-day period, and found
an improvement in oxygen-support class in 68% of patients. In
median 18 days of follow-up, 57% patients were extubated, 47%
were discharged, whereas 13% of them died.6
Antinori et al. conducted a prospective open-label study in
35 severe COVID-19 patients. Overall, 63% completed the 10-day
course of remdesivir and 22.8% discontinued treatment due to
adverse events (AEs). At day 28, 82.3 and 33.3% of patients from the
ward (n = 17) and the ICU (n = 18) were discharged whe reas 5.9 and
44.8% died. Hyp ertransaminasemia (42.8%) and acute kidney injury
(22.8%) were the frequently encountered severe AEs.7
A double-blind, multicenter, placebo-controlled RCT was
performed by Wang et al. in adults with severe COVID-19
infection. Compared to placebo, remdesivir was not associated
with signicant improvement in time to clinical improvement.
In patients with symptom duration of ≤10 days, time to clinical
improvement was numerically fas ter but statistically nonsignicant
with remdesivir. The author concluded that there was a need for
further studies to conrm whether early initiation of remdesivir
results in clinical improvements.8
A recent trial showed a shortened time to recovery in patients
admitted with evid ence of lower respiratory tract involvement with
COVID-19, with the use of remdesivir as comp ared to placebo [11 vs
15 days [(rate ratio for recovery, 1.32; 95% CI, 1.12–1.55; p < 0.0 01)].
There were no signicant adverse eects as well with remdesivir.
However, it remains to be seen if this eect per sists in patients with
severe COVID-19.9
On June 1, 2020, the Indian regulatory authority—Drug
Controller General of India (DCGI)—has granted “restricted
emergency use” of remdesivir in hospitalized COVID-19 patients.10
Lopinavir/ritonavir
Lopinavir is an antiretroviral drug used in combination with
ritonavir, which is a booster agent. In an in vitro study, lopinavir
showed an antiviral eect against the SARS-CoV-2 virus in Vero
E6 cells.11
In a study from Ye et al. involving 47 patients, compared to the
standard of care, the addition of lopinavir/ritonavir to the standard
of care resulted in a shorter tim e for temperature reduction as well
as a less number of days (7.8 ± 3.09 days vs control: 12.0 ± 0.82
days, p = 0.0219) necessary for the negative report on SARS- CoV-2.
The authors suggested use of this combination along with other
pneumonia adjuvant drugs in COVID-19 treatment.12
Another study from Li et al. assessed the ecacy and safety of
lopinavir/ritonavir (n = 34) or arbidol (Umifenovir) monotherapy (n =
35) in mild to moderate cases. Compared to the control populatio n
(n = 17), there was no signicant benet with either therapy in the
primary endpoint of the rate of positive-to-negative conversion of
SARS-CoV-2 nucleic acid. Additionally, there were no dierences
in groups with regards to rates of antipyresis, cough alleviation, or
improvement of chest CT at days 7 or day 14.13
In an open-label RCT involving 199 hospitalized patients
with severe COVID-19, Cao et al. found no dierence in control
(standard care) and lopinavir/ritonavir treatments, for time to
clinical improvement or mortality at day 28. The frequency of
gastrointestinal side eects (13.8%) was more with combination
treatment, leading to discontinuation of therapy.14
Umifenovir
Umifenovir is a hemagglutinin inhibitor that blocks the inuenza
virus entry in the host cell. It also stimulates the endogenous
production of interferon against virus replication, enhances the
phagocytic function of macrophages, and activates natural killer
cells.15,16
In 81 patients with COVID-19, Lian et al. performed a
retrospective study comparing umifenovir (n = 45) to the no
treatment (n = 36) group. There was no difference to time to
negativity of COVID-19, RT-PCR in either group at 7 days or overall;
however, hospital length of stay (LOS) was signicantly longer with
umifenovir.17
Table 1: Currently drugs under investigation for treatment of COVID-19
Drug class Molecules
Antiviral drugs Remdesivir
Lopinavir-ritonavir
Favipiravir
Others (umifenovir, ribavarin, oseltami-
vir)
Repurposed as antiviral
drugs Chloroquine/hydroxychloroquine ±
azithromycin
Nitazoxanide
Ivermectin
Doxycycline
Nafamostat, camostat
Immunomodulatory drugs Steroids
Tocilizumab, sarilumab
Interferon-1
Bevacizumab
Fingolimod
Eculizumab
Ulinastatin
Itolizumab
Adjunctive therapies Anticoagulant (LMWH/UFH)
High-dose IV vitamin C
Convalescent plasma
CytoSorb
Vaccines
COVID-19: Therapy and Prevention. Indian J Crit Care Med 2020;
24(9):838–846.
Source of support: Nil
Conict of interest: None

Current Approaches to COVID-19: erapy and Prevention
Indian Journal of Crical Care Medicine, Volume 24 Issue 9 (September 2020)
840
Favipiravir
Favipiravir (FPV), a pyrazine carboxamide derivative, is a novel
broad-spectrum antiviral, which is used for the treatment of
inuenza.18 In an open-label study, Cai et al. compared the eects
of FPV to lopinavir/ritonavir for the treatment of COVID-19. The FPV
(n = 35) dose was 1600 mg twice daily on day 1 and 600 mg twice
daily from day 2 to 14. The lopinavir/ritonavir (n = 45) dose was 400
mg/100 mg twice daily for 14 days. Interferon- α was coadministered
by aerosol inhalation (5 million U twice dail y) in both arms. T he viral
clearance time was signicantly shor ter in the FPV arm (4 days vs 11
days, p < 0.001), which was also seen in the multivariate analysis.
The chest imaging improvement rate was signicantly greater in
the FPV arm (91.43% vs 62.22%, p = 0.004), which persisted even
after adjustment for potential confounders. Fewer AEs were seen
with the favipiravir arm as compared to control.19
In India, FPV is under evaluation in phase III, open-label,
randomized study (CTRI/ 2020/05/02511) compared to the standard
of care in adult patients with mild to moderate COVID-19.20
Ribavirin
Ribavirin, a guanosine analog, interferes with the replication of
RNA and DNA viruses. Favorable clinical outcomes with the use
of ribavirin have been indicated in SARS-CoV and MERS-CoV
outbreaks.21 In a multicenter, prospective, open-lab el, randomized,
phase 2 trial from China, Hung et al. compared the combination of
therapy with lopinavir/ritonavir, ribavirin, and interferon β-1b (n =
86) with lopinavir/ritonavir (control, n = 41). The median duration
from symptom onset to starting therapy was 5 days. The primary
endpoint, i.e., median t ime to nasopharyngeal swab negativ ity, was
signicantly shorter in combination treatment (7 days vs 12 days,
p = 0·0010). Adverse events were limited to nausea and diarrhea.
There were no deaths reported in any group. They concluded that
early combination therapy can achieve faster defervescence.22
Oseltamivir
Oseltamivir in its active form inside the body binds to and inhibits
the active site of the neuraminidase enzymes that are present
on all inuenza viruses.23 Considering the highly selective action
of oseltamivir in inuenza viruses, it is expected to be less likely
eective in COVID-19. In a Chinese observational study, where 89.9%
(out of 138) patients were given oseltamivir, there was no eect on
clinical outcomes.24
other drugs repurposed As AntIVIrAl
drugs
Antimalarial Drugs
Chloroquine/hydroxychloroquine
Chloroquine (CQ) or hydroxychloroquine (HCQ) may act by multiple
mechanisms. It inhibits the pre -entry step by inhibiting viral p article
binding to cellular receptors, impairing the early stage of viral
replication by changing the pH in endosomes, and interfering
with posttranslational modication of viral proteins. In addition,
immunomodulatory eects by virtue of inhibition of interleukins
(ILs) such as IL-1beta and IL-6 also contribute to reducing the
inammatory response to SARS-CoV-2.25
An in vitro study demonstrated that half maximal eective
concentration (EC50) for SARS-CoV-2 with CQ was lower than HCQ,
indicating both were capable of in vitro inhibition.26
A large observational study from New York, which included
1,376 patients, of whom 811 (58.9%) received HCQ within 48
hours of hospitalization, found that there was no association of
treatment with HCQ and the primary endpoint, i.e., death or need
for intubation, over a median follow-up period of 22.5 days.27
Horby and Landray, the principle investigators of the R ecovery
Trial, reported the results of the interim analysis. To date, 1,542
patients were randomized to HCQ and 3,132 to usual care. There
was no eect on 28-day mortalit y [25.7% HCQ vs 23.5% usual care;
HR 1.11 (95% CI 0.98–1.26, p = 0.10)] or on hospital LOS. Therefore,
the recruitment to HCQ was stopped.28 Whether HCQ given early
in asymptomatic COVID-19 or patients with mild illness remains
to be seen.
Hydroxychloroquine Plus Azithromycin
Some investigators have used azithromycin (AZT) in addition to
HCQ in suspected bacterial superinfection.
A very small study fro m Molina (11 hospitalized patients) looked
at outcomes of patients treated with H CQ and AZ T. In these patients ,
nasopharyng eal swabs remained positive for SARS- CoV-2 RNA even
after 5–6 days of beginning the treatment.29
In an early study from France, which was an open-label study
in 36 COVID-19 patients, the authors found a signicant 100% viral
clearance with HCQ-AZ T on day 6, as compared to lower clearance
rates with HCQ alone (57.1%) or the control group (12.5%). This study
has been widely criticized in the literature since its publications
(p < 0.001).30 In fact, the International Society of Antimicrobial
Chemotherapy (ISAC) published a statement on the IACC paper
on its website, which stated, “ISAC shares the concerns regarding
the above article published recently in the International Journal
of Antimicrobial Agents (IJAA). The ISAC Board believes the article
does not meet the So ciety’s expected standard, e specially relating
to the lack of better explanations of the inclusion criteria and the
triage of patients to ensure patient safety.”31
A recent retrospective multicenter trial from Rosenberg et
al. compared the in-hospital mortality rate in 1,438 hospitalized
patients, with HCQ plus AZT (735 patients) compared to HCQ (271
patients) or AZT (211 patients) alone or no therapy (221 patients).
The mortality rates in these four groups were 25.7, 19.9, 10, and
12.7%, respectively. Compared to the control arm, the risk of cardiac
arrest was signicantly higher with the combination therapy, but
not with either drugs used alone.32
Because of the increased risk of QT prolongation and cardiac
death with concomitant use of HCQ and AZ T, the American College
of Cardiology, the American Heart Association, and the Heart
Rhythm Societ y suggested QT assessment and monitoring protocol
for studies conducted with two drugs together.33,34 DeJong and
Watcher in their editorial raise a concern that amidst the rising toll of
COVID-19, healthcare settings are under enormous and understandable
pressure to do something for it. We must understand the potential use
of any therapy should be based on medicine and the notion should
rst do no harm. Best way to protect the patients is to stay grounded
in evidence and to ght misinformation.35
Antiprotozoal Drugs: Nitazoxanide
It is a broad-spec trum antiparasitic agent, which is being sugges ted
for treatment of inuenza and other viral respiratory infections.36
Some investigators have suggested the use of nitazoxanide in
COVID-19 in combination with AZT and HCQ,37,38 but no clinical
studies have yet been performed. Though potential evidence from

Current Approaches to COVID-19: erapy and Prevention
Indian Journal of Crical Care Medicine, Volume 24 Issue 9 (September 2020) 841
in vitro studies is suggestive, lack of clinic al studies makes it dicult
to determine its recommendation in COVID-19.
Antiparasitic Drugs: Ivermectin
An in vitro study from Caly et al. demonstrated that ivermectin
inhibits the SARS-CoV-2.39
However, there are concerns about the therapeutic levels of
drug being achieved in the usual doses.40 Currently, there is one
comparative ongoing trial (NCT04391127) of this drug (comparison
with HCQ, placebo, three arms) for treatment of COVID-19.41
Antibiotics: Doxycycline
Coronavirus is known to bind to metalloproteases (MMPs) of
the host to ensure viral survival. Commonly used antibiotics like
doxycycline (tetracycline) is known to chelate zinc from MMPs.
This chelating property of doxycycline may help inhibit COVID-19
infection. In France, a phase III r andomized, double-blind placeb o-
controlled clinical study is currently recruiting nonhospitalized
patients with COVID-19 to confirm the safety and efficacy of
doxycycline (ClinicalTrials.gov Identier: NCT04371952).42
Serine Protease Inhibitors: Camostat, Nafamostat
The host cell protease TMPRSS2 is necessary for SARS-CoV2 spike
protein receptor priming for its eective attachment to the ACE2
receptor.43 Given these observation, inhibition of TMPRSS2 with
serine protease inhibitors like camostat and nafamostat can be
a potential option to prevent SARS-CoV-2 viral entry in host cells.
These drugs are undergoing clinical trials in various countries for
their eectiveness against COVID-19.44 In India, a clinical study of
nafamostat in patients with Covid19 is recently been approved by
DCGI.45
Immunomodulatory Drugs
Besides viral factors, the host immune response plays an
essential role in disease progression. Li et al. suggested that
immunopathogenesis in response to the dysregulated immune
response leads to disease progression . In the incubation period and
early stage of the disease, a spe cic adaptive immune response may
preclude the disease progression. In some situations, the cy tokine
release syndrome (CRS) in the later stages of the infection leads
to more severe disease.46 Multiple factors such as age, underlying
comorbidities, secondary infections, and elevated inammatory
indicators can predict the mortality in COVID-19. Virus-activated
“cytokine storm s yndrome” or fulminant myocarditis are considered
to be the cause of death in COVID-19.47 Therefore, modulating the
immune response is a potential therapeutic target in COVID-19
patients.
Corticosteroids
Guidelines from the Society of Critical Care Medicine and the
European Society of Intensive Care Medicine (SCCM-ESICM)
indicated use of low-dose systemic corticosteroids for a short
period only in mechanically ventilated COVID-19 patients with
acute respiratory distress syndrome (ARDS).48 The WHO advised
against the use of steroids in patients with COVID-19.2 This WHO
recommendation is probabl y because of the lack of clinical evidence
pertaining to corticosteroids in COVID-19.
A single-center, retrospective study from China by Wang et al.
showed that among 138 cases of conrmed COVID-19 pneumonia,
44.9% received corticosteroids and were administered in a
signicantly higher proportion of patients admitted to ICU than
non-ICU setting (72.2% vs 35.3%, p < 0.0 01).24
A study from Zha et al. from China , 11 of 31 severe patients with
COVID-19 who received cor ticosteroid treatment, demonstrated no
association between steroid treatment and virus clearance time,
length of hospital stay, or duration of symptoms.49
A retrospective study by Wu et al. involving COVID-19 patients
with pneumonia identied that in patients with ARDS, treatment
with methylprednisolone was associated with a 62% relative risk
reduction of mortality.50
These data indicate that more severe the disease, there is a
greater likelihood of steroid us e. Villar et al. consider that in patients
of COVID-19 with ARDS, corticosteroids can be lifesaving in severe
life-threatening cytokine storm.51
In a recent study involving moderate to severe COVID patients
(n = 213), Fadel et al. demonstrated that compared to the standard
of care, the early corticosteroid treatment (methylprednisolone
0.5–1 mg/kg/day divided in two doses for 3 days) signicantly
lowered the rate of the composite endpoint, i.e., escalation of care
from ward to ICU, a new requirement for mechanical ventilation,
and mortality (34.9% vs 54.3%, p = 0.005). The benets were also
reported with individual outcomes.52 This clearly indicates that
a short course of low-dose steroids is eective in reducing the
mortality and other outcomes in COVID-19.
News released by the principle investigators of the Recovery
Trial said that dexamethasone is the rst drug, which has shown
reduction in the mor tality in patients with COVID-19. They compared
mortality in 2,104 patients randomized to dexamethasone 6 mg
once a day (either by oral or intravenous route) for 10 days and
4,321 patients randomized to usual care alone. It was found that
dexamethasone reduced the risk of 28-day mortality by 17% with
a highly signicant trend showing greatest benet among those
on ventilators. No evidence of benefit was found for patients
who did not receive oxygen. The baseline 28-day mortality for
patients on usual care was 41% in ventilated patients, 25% on
oxygen therapy, and 13% on those who were not receiving any
respiratory intervention. Dexamethasone has several advantages
over methylprednisolone, pure glucocorticoid as against
methylprednisolone, which has additional mineralocorticoid
activity, which can be bad for ARDS patients due to uid retention
and it is ve times more potent than methylprednisolone with
profound anti-inammatory proper ties. Results of this study would
be published soon.53
Interleukin-6 Inhibitors: Tocilizumab
Tocilizumab (TCZ) targets the IL-6 receptors and blocks their
action. It has proved its safety and eectiveness in the treatment
of rheumatoid arthritis.54
In a retrospective study on 15 patients (two moderately ill, six
seriously ill, and seven critically ill) from China, Luo et al. observed
that of the four critically ill patients treated with only a single dose,
three died and one patient did not show a decline in C-reactive
protein levels. Clinical stabilization was achieved in 10 patients,
whereas disease progression was reported in 2 cases.55
Xu et al. reported outcomes in 21 severe COVID-19 patients
who were treated with TCZ; 75% had decreased FiO2 requirement
and lung opacities were resolved in most (90.5%) patients within
5 days. The elevated CRP levels reduced signicantly in 84.2% of
patients. After a m ean of 15.1 days after tocilizumab administration,
all patients were discharged and there were no obvious adverse

Current Approaches to COVID-19: erapy and Prevention
Indian Journal of Crical Care Medicine, Volume 24 Issue 9 (September 2020)
842
reactions.56 This data indicate the potential benets of to cilizumab
in lowering mortality in severe COVID-19 patients.
A prospective single -arm multicenter study in 63 adult patients
with severe COVID-19 demonstrated that TCZ administration within
6 days from admission increased the likelihood of survival.57
In an Italian study, 100 consecutively patients with conrmed
COVID-19 pneumonia were given two IV infusions of tocilizumab
12 hours apart. Of the 57 patients treated in ward, 35 patients
improved and NIV could be stopped, 7 continued on to be
stable on NIV, while 13 patients worsened. Overall, after 10 days
of follow-up, 77 patients had improved or stabilized respiratory
condition. Among 61 of these 77, signicant clearing of diuse
bilateral opacities was repor ted. Remaining 23% patients worsened
and 20 of them died. The study concluded that the response to
tocilizumab was rapid, sustain ed, and resulted in signicant clinical
improvement.58
Clinical trials for another IL-6 inhibitor, Sarilumab (ClinicalTrials.
gov Identifier: NCT04327388, ClinicalTrials.gov Identifier:
NCT04315298), in severe COVID-19 patients are underway.59,60
Interferon-1
Type 1 interferons (IFN-I) are a group of cytokines comprising of
the various subtypes such as α, β, ε, ω, and κ.61 Antiviral eects
of it are majorly mediated by inducing the production of antiviral
eector proteins, which in hibit viral replication and activate cellular
immunity by promoting proliferation and activation of cytotoxic
T lymphocytes (CTL) and activating natural killer (NK) cells and
macrophages to clear the virus.62
SARS-CoV-2 displays a substantial sensitivity to IFN-α and
especially IFNα2b nasal drop/sprays can reduce the infection rate.
It indicates IFN-I can b e used as a prophylaxis against SARS- CoV-2.61
Experts from China recommend administering 5 million U of
IFNα by vapor inhalation twice a day to the patients, especially in
combination with ribavirin.63 As dis cussed above, a trial from Hung
et al. demonstrated better defervescence with a combination of
lopinavir/ritonavir (400/100 mg every 12 hours), ribavirin (400 mg
every 12 hours), and interferon beta 1b (three doses of 8 million
international units on alternate days).22
Bevacizumab
Recent report s indicated that the levels of the vascular endothelial
growth factor (VEGF) are increased in COVID-19. As one of the
most potent vascular per meability inducer, VEGF can contribute to
pulmonary ede ma and progressive lung disease. With this rationale,
Bevacizumab, an anti-VEGF drug, is now under investigation for
use in COVID-19. BEST-CP is an ongoing open-label clinical trial
(ClinicalTrials.gov Identier: NCT04275414) in COVID-19 patients,
with inammatory exudation or pleural eusion.64
Fingolimod
Fingolimod is a sphingosine-1-phosphate receptor regulator,
which is widely used in multiple sclerosis. As COVID-19 patients
develop pulmonary edema and hyaline membrane from within
lungs, immune modulator use along with ventilator support may
be considered in managing such patients. A phase 2 clinical trial
is underway in patients with COVID-19 pneumonia (ClinicalTrials.
gov Identier: NC T04280588) using ngolimod (0. 5 mg orally once
daily, for 3 consecutive days) to assess the lesion change on X-ray
images from day 5 to baseline.65
Eculizumab
Eculizumab is a long-acting humanized monoclonal antibody that
inhibits cleavage of C5 into C5a and C5b. Thus, deployment of the
terminal complement system is inhibited including the formation
of the membrane attack complex.66
In a case series of four patients with SARS-CoV-2 infection
and severe pneumonia or ARDS, Diurno et al. showed that four
infusions of eculizumab in addition to enoxaparin, lopinavir/
ritonavir, HCQ, ceftriaxone, and vitamin C for 4 days resulted in a
successful outcome in all patients. Mean C reactive protein levels
dropped from 14.6 mg/dL to 3.5 mg/dL and the mean duration of
the disease was 12.8 days.67
A clinical study (ClinicalTrials.gov Identier: NCT04288713) is
underway for evaluating the safety and ecacy of Eculizumab in
COV ID-19 patient s.68
Ulinastatin
Ulinastatin is a broad-spectrum serine protease inhibitor that is
currently available for the treatment of severe sepsis and mild to
severe acute pancreatitis. The 2019 Shanghai Expert consensus
recommends ulinastatin for the prevention and treatment of
cytokine storm in COVID-19.69 Besides its effect on reduction
in levels of TNF-α, IL-1β, IL-6, and IL-8, ulinastatin has conrmed
signicant ecacy in removing oxygen free radicals, improving
microcirculation and tissue perfusion, and alleviating endothelial
injuries.70,71 A phase II placebo-controlled study with ulinastatin
infusion has been proposed in the United States by Stanford
University (ClinicalTrials.gov Identier: NCT04393311).72 In India,
DCGI recently approved a protocol for conduc t of a phase III clinical
study of ulinastatin in COVID-19 patients with mild to moderate
ARDS.73
Itolizumab
Itolizumab is a humanized recombinant anti-CD6 monoclonal
antibody that is indicated in psoriasis management. Itolizumab
has a potent anti-inammatory eect reducing the production
of pro-inammatory cytokines IL-6, TNF, IFNγ, and IL. It could be
an attractive therapeutic option to control the cytokine storm in
patients with COVID19.74 Itolizumab is under phase II clinical study
in India for the management of m oderate to severe ARDS in patients
with COVID-19 disease (CTRI Identier: CTRI/2020/05/024959).75
Adjuvant Therapies
Vitamin C
The expert consensus from the Shanghai medical association
recommends that 100–200 mg/kg intravenous (IV) vitamin C daily
can lead to an improvement in the oxygenatio n index.69 By virtue of
its actions on oxidati ve stress and inammation and immunological
function, vitamin C has shown ecacy in patients of sepsis with
ARDS. In the CITRIS-ALI trial involving patients of sepsis and ARDS
(n = 167), IV infusion of vitamin C (50 mg/kg in dextros e 5% in water
over 96 hours) resulted in signicantly lower 28-day mortality
(29.8% vs 46.3%, p = 0.03).76
Heparin/low-molecular-weight Heparin
In COVID-19, there is no typical disseminated intravascular
coagulation, but there is formation of local microthrombi in lung
and other organs. Disruption of the endothelium in viral infection,
along with a virus-induced increase in von Willebrand factor

Current Approaches to COVID-19: erapy and Prevention
Indian Journal of Crical Care Medicine, Volume 24 Issue 9 (September 2020) 843
levels, activation of the toll-like receptor, and the tissue factor
pathway lead to the formation of brin clots. In addition, the long
duration of bed rest in COVID-19 may increase chances of venous
thromboembolism.77
Heparin with its anticoagulant and anti-inammatory (bind
to inammatory cytokines, inhibition of neutrophil chemotaxis,
and leukocyte migration) properties can reduce the inammatory
response in COVID-19.78 Tang et al. demonstrated that in patients
with SARS-CoV-2, heparin was benecial in reducing mortality in
patients who met the criter ia for sepsis-induced coagulopathy. The
majority of the patients received low-molecular-weight heparin
(LMWH).79 Atallah et al. proposed a patient-tailored algorithm
for coagulopathy. In patients at high risk of thromboembolism,
continuous heparin infusion or enoxaparin BD was advised.77
The International Society on Thrombosis and Haemostasis
(ISTH) recommends thrombo prophylaxis with LMWH in hospitalized
COVID-19 patients. 80 Revised guidelines from the Ministry of
Health and Family Welfare India recommended pharmacological
prophylaxis LMWH or heparin (5,000 units subcutaneously twice
daily) in adults and adolescents.81
Convalescent Plasma
In ve critically ill COVID-19 patients, transfusion with convalescent
plasma with a SARS-CoV-2-specic antibody (IgG) binding titer
greater than 1:1,000 and a neutralization titer greater than 40
resulted in negative viral load within 12 days. ARDS resolved in
four out of ve patients on day 12 of transfusion. This indicates
convalescent plasma may be useful in clinical recovery of critically
ill patients.82
The United States Food and Drugs Administration issued
guidelines for the use of investigational COVID-19 convalescent
plasma. Criteria laid down for eligibility for the use of convalescent
plasma are laboratory-confirmed, severe COVID-19 (dyspnea,
O2 saturation ≤93%, respiratory rate ≥30 per minute, the partial
pressure of arterial ox ygen to fraction of inspired oxygen ratio <300
and lung inltrates >50% within 24–48 hour s) or a life-threatening
COVID-19 (respiratory failure, se ptic shock, multiorgan dysfuncti on)
disease along with an inform ed consent provided by the patient or
healthcare proxy.83 The Indian Council of Medical Research (ICMR)
has initiated PLACID Trial (CTRI/2020/04/024775), which is a phase
II study to assess the safet y and ecacy of convalescent plasma to
limit COVID-19-associated complications. As of May 22, 2020, the
ICMR has approved 46 sites. Total of 452 patients will be recruited
into the study.84
CytoSorb
Cytosorb is an extracorporeal cytokine adsorber. Either stand-alone
or with renal replacement therapy, it has been used in COVID-19
patients in China, Germany, the United States, Italy, and other
countries. It has been approved by the FDA (United States) and
DCGI (India) for use in COVID-19 and is recommended in Panama
and Italian Nephrology guidelines for COVID-19.85
Vaccines
In a race to develop the effective vaccine to control the further
spread of COVID-19, there are nearly 118 candidate vaccines
identified globally, out of which 8 are already in phase I/II of
clinical evaluation and remaining in the preclinical phase.
Two vaccine candidates have successfully completed phase I
of clinical development. The first is Ad5-nCoV from CanSino
Biologicals in China and the second one is mRNA-1273 from
Moderna in the United States.86 In India, nearly 14 private and
academic institutes are in hunt for developing the vaccine for
COVID-19.87 Apart from these, the BCG (Bacillus Calmet te-Guerin)
vaccine is under clinical study for COVID-19 in countries like
Australia, Germany, and India. It is based on reports of some
epidemiological studies suggesting countries with mandatory
BCG inoculation for tuberculosis may be experiencing fewer
cases and mortality due to COVID-19.88
conclu s I o n
COVID-19 pandemic is aec ting an increasing number of people. A
number of antivirals, immunomodulators, and adjuvant therapies
are being proposed for us e in the management of COVID-19. Based
on available evidence, we consider few of th e discussed treatments
have potential to be considered in majority of the patients with
COVID-19. Table 2 enlists such therapies with disease s tage and our
remarks about their use. It is possible that the early use of antiviral
agents may be useful in improving clinical conditions. Among
dierent antiviral agents, remdesivir shows promise in COVID-19.
Though HCQ has been widely used and recommended in treatment
of COVID-19, recent observations from RCTs indicate no benet in
terms of mortality outcomes. However, the ICMR advises HCQ use
for prophylaxis of COVID -19 in high-risk individuals such as HCWs. 89
Immunomodulatory therapies such as tocilizumab may be tried in
moderate to severe and critically ill patients to control cytokine
storm and possibly reduce disease progression. The use of LMWH
is advised in both prophylactic and therapeutic doses in select
patients. Trials of multiple vaccines are currently und erway, but will
take at least few more months before they are intro duced for clinical
use. Adhering to basic principles of cr itical care, till evidence-based
treatment for COVID-19 becomes available, should be the way to
go. Adjuvant therapies may be tried in selected patients, with full
disclosure to the patient and family, since these therapies may be
expensive. With currently available ther apies with other indications
such as vitamin C, ulinast atin, etc., there is need to generate furth er
evidence for their use in COVID-19.
Table 2: Potential current treatments tailored to disease severity
Therapy Disease stage Authors remarks
Remdesivir Moderate and severe Initiate early in disease course
Hydroxychloroquine Mild, moderate, and severe Current evidence contradictory to opine for or against the use of HCQ
Corticosteroids Moderate, severe, and critically ill Low dose (e.g., methylprednisolone 0.5–1 mg/kg/day divided in two
doses for 3 days or dexamethasone 6 mg OD by either oral or IV route
for 10 days)
Tocilizumab Moderate, severe, and critically ill Consider two infusions 12 hours apart
Heparin/LMWH Mild, moderate, severe, and critically ill Use dosage tailored on the risk of thromboembolism
Convalescent plasma Severe and critically ill Consider it whenever available

Current Approaches to COVID-19: erapy and Prevention
Indian Journal of Crical Care Medicine, Volume 24 Issue 9 (September 2020)
844
Acknowledgments
We thank Dr Vijay Chamle (Head, Medical Affairs, Urihk
Pharmaceuticals, Mumbai) and Dr Vijay Katekhaye (Quest
MedPharma Consultants, Nagpur) for their contribution to the
drafting and reviewing of the manuscript.
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