Introduction

No acute respiratory syndrome coronavirus-2 (SARS-CoV-2) originated from Wuhan,

Hybrid Province, China. The infection has spread very rapidly around the word. WHO
declared the coronavirus-2 (SAR-CoV-2) epidemic is a public health emergency of
international concerns. WHO officially announced the name of coronavirus disease as
covid-19 on February 11,2020.WHO declared the severe outbreak of COVID-19 as
pandemic on March 11,2020.The outbreak of COVID-19 caused serious global health
emergency. It has affected more than 200 countries. Coronavirus-2 (SARS-CoV-2) has
causing serious morbidity and mortality. Betacoronavirus is the family of severe acute
respiratory syndrome coronavirus-2 (SAR-CoV-2) .This coronavirus-2 is more
threatening than severe acute respiratory syndrome (SARS) coronavirus and middle
east respiratory syndrome (MERS) coronavirus. The COVID-19 common
manifestations include dry cough, sore throat, tiredness, fever, loss of taste or smell,
pain, and serious symptoms include shortness of breath, loss of speech and
movement. COVID-19 disease is distinguished as strange pneumonia. Coronaviruses
are spherical in shape and possess crown-like spikes on their surface. SAR-CoV-2 is a
single stranded RNA virus. SAR-CoV-2 encrypts spike S protein which contains receptor
binding domain (RBD). The glycoprotein spikes (S) binds to the angiotensin converting
enzyme 2 (ACE2) and by membrane fusion intakes the virus into human cell. This
project will summarize the most current pharmacotherapeutics prescribed in the
treatment of severe cases of COVID-19 patients. These include antiviral therapy,
antibiotics, systemic corticosteroids and anti-inflammatory drugs (including
antiarthritis drugs), neuraminidase inhibitors, RNA synthesis inhibitors, convalescent
plasma, and traditional herbal medicines. In the absence of definitive and specific
treatment regimens ,strategies including early diagnosis, timely reporting, isolation,
and supportive treatments are important line of actions against COVID-19 infections.
Current social practices including timely release of epidemic information and
maintenance of social orders and personal practices such as improving personal
hygiene, wearing facial coverings or masks, adequate rest, and keeping rooms well
ventilated remain some of first line of actions against COVID-19 pandemic. At present,
the treatments of patients with SARS-CoV-2 infection are mainly repurposing the
available therapeutic drugs and based on symptomatic conditions. Considering ARDS,
followed by secondary infections, antibiotics,
antiviral therapy, systemic corticosteroids, and anti-inflammatory drugs (including
anti-arthritis drugs) are often used in the treatment regimens. In addition to antiviral
interferers and antibiotics, neuraminidase inhibitors, RNA synthesis inhibitors,
convalescent plasma, and traditional herbal medicines have also been utilized in the
treatment of COVID-19. Nevertheless, the efficacy of these treatment regimens
remains to be verified by appropriately designed clinical trials.

Antiviral Therapy

At present, no effective antiviral drugs have been found, but some drugs appear to
have certain therapeutic effects according to clinical observation and study. Using
more than 3 antiviral drugs at the same time is not recommended. When drugs
have intolerable adverse effects, they should be discontinued .

Remdesivir

Remdesivir is an RNA-dependent polymerase inhibitor tested for efficacy in

treatment of SARS-CoV-2 infection and has demonstrated the most promising anti
viral therapeutic results.Unlike other nucleotide analogues, remdesivir is a
phosphoramidate prodrug with broad-spectrum activity against many viruses, such
as Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae (SARS CoV
and Middle East respiratory syndrome coronavirus [MERSCoV]) .
Remdesivir was initially developed by Gilead Sciences in 2017 as treatment for Ebola
virus infection. Several phase 3 trials were initiated to evaluate the role of remdesivir
for severe and moderate disease in the USA, South Korea and China. Recently the
results of a doubleblind, randomized, placebo-controlled trial of intravenous
remdesivir in adults hospitalized with Covid-19 disease and evidence of lower
respiratory tract involvement were reported (ACCT-1 trial). Patients were randomly
assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100
mg daily for up to 9 additional days) or placebo for up to 10 days. The primary
outcome was time to recovery, and this was defned as either discharge from the
hospital or hospitalization only for infection-control. 1063 patients were randomized.
The safety monitoring committee recommended early unblinding on the basis of data
that showed shorter time to recovery in the remdesivir arm. 538 patients were
assigned to remdesivir and 521 to placebo. The remdesivir group had a median
recovery time of 11 days (95% CI 9 to 12), as compared with 15 days (95% CI 13 to
19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI
1.12 to 1.55; p<0.001). The mortality estimation with Kaplan–Meier by 14 days was
7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI
0.47 to 1.04). 114 of 541 patients in the remdesivir group reported serious adverse
events . Another ongoing phase 3 randomized, double-blind, placebo controlled,
multicenter study is evaluating the efcacy and safety of remdesivir in 452 hospitalized
adult patients with severe respiratory disease . The results of this trial are anticipated.
On May 1, 2020, The US FDA based on the results of the ACTT trial issued an EUA of
remdesivir on April 29th 2020 to allow emergency use of the agent for severe COVID-
19 (confirmed or suspected) in hospitalized adults and children. A phase 1b trial of
an inhaled nebulized version was initiated in late June 2020 to determine if
remdesivir can be used on an outpatient basis and at earlier stages of the disease.
Post ACTT trial announcement the results from a smaller randomized trial which was
conducted in China were reported. This was a randomized, double-blind, placebo
controlled, multicenter trial (n=237; 158 remdesivir and 79 placebo; 1 patient
withdrew) which demonstrated that remdesivir was not associated with statistically
signifcant clinical benefit, measured as time to clinical improvement, in adults
hospitalized with severe disease. Although not statistically significant, patients
receiving remdesivir had a numerically faster time to clinical improvement than those
receiving placebo among patients with symptom duration of less than 10 days. The
authors concluded this trend in reduction in time to clinical improvement in those
treated earlier requires confirmation in larger studies. The open-label phase 3
SIMPLE trial (n=397) in hospitalized patients with severe COVID-19 disease not
requiring mechanical ventilation demonstrated similar improvement in clinical
condition with the 5-day remdesivir regimen compared with the 10-day regimen on
day 14 (OR: 0.75 [95% CI 0.51–1.12]). In this study, 65% of patients who received a 5-
day course of remdesivir showed a clinical improvement of at least 2 points on the 7-
point ordinal scale at day 14, compared with 54% of patients who received 10-day
course. The study demonstrates that possibly some patients could be treated with a
5 day regimen, which could significantly expand the number of patients who could
be treated with the current supply of remdesivir. The trial is continuing with an
enrollment goal of 6000 patients . Similarly, the phase 3 SIMPLE II trial in patients
with moderate COVID
19 disease showed that 5 days of remdesivir treatment was 65% more likely to yield
clinical improvement at day 11 than standard of care (p=0.18). These data show that
early intervention with a 5-day treatment course can significantly improve clinical
outcomes. The first published report regarding remdesivir compassionate use
described clinical improvement in 36 of 53 hospitalized patients (68%) with severe
COVID-19. At baseline, 30 patients (57%) were receiving ventilation and 4 (8%)
extracorporeal membrane oxygenation (ECMO) . Additional data for compassionate
use of remdesivir were released on July 10, 2020 and demonstrated that remdesivir
treatment was associated with significantly improved clinical recovery and a 62%
reduction in the risk of mortality compared with standard of care. Findings from the
comparative analysis showed that 74.4% of remdesivir treated patients recovered by
day 14 versus 59% of patients receiving standard of care. The mortality rate in
patients treated with remdesivir in the analysis was 7.6% at day 14 compared with
12.5% among patients not taking remdesivir (adjusted OR 0.38; 95% CI 0.22–0.68,
p=0.001).
Lopinavir‑ritonavir
Lopinavir-ritonavir is an HIV protease inhibitor and is indicated in combination with
other antiretroviral products for the treatment of human immunodefciency virus
(HIV-1) infected adults, adolescents and children above the age of 2 years. In 2004,
an open label study suggested that the addition of lopinavir–ritonavir to ribavirin
reduced the risk of adverse clinical outcomes (defined as acute respiratory distress
syndrome [ARDS] or death) as well as viral load among patients with SARS . The
comparison arm in this study was a historical control group that was treated only
with ribavirin. The main limitations of the study were that it was an open label study
without randomization design and patients were concurrently treated with
glucocorticoids and ribavirin, making the pure effect of lopinavir-ritonavir difficult to
assess. Lopinavir-ritonavir has also showed activity both in vitro and in animal models
against Middle East respiratory syndrome and it is now studied in humans with MERS
in combination with recombinant interferon 1b in a study that has completed accrual.
The results of the study are anticipated.In a phase 2 study recently published in ‘The
Lancet’ a total of 127 patients, with mild to moderate COVID-19 infection were
randomized 2:1 to receive either a 14-day combination of lopinavir 400 mg and
ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million
international units of interferon beta-1b on alternate days (combination group) or 14
days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary
endpoint was time to achieve negative nasopharyngeal swab for SARS-CoV-2 with
RT-PCR. The median number of days from symptom onset to study enrolment and
treatment initiation was 5 days. The results of this study showed that the
combination therapy was more effective as the median time from treatment
initiation to negative nasopharyngeal swab was 7 days [IQR 5–11] for the
combination group and 12 days for the control group; (hazard ratio 4.37 [95% CI
1.86–10.24], p=0.0010). The authors suggested that early triple antiviral therapy
might be effective in mild to moderate illness. The combination of lopinavir-ritonavir
with or without ribavirin has been recommended as a treatment option for novel
coronavirus, especially in countries that have been hit hard by the disease. In a trial
by Cao et al., patients with oxygen saturation of 94% or less (while they were
breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of
inspired oxygen (Fio2) was less than 300 mm Hg) were randomly assigned in a 1:1
ratio to receive either lopinavir– ritonavir (400 mg and 100 mg, respectively) twice a
day for 14 days, in addition to standard of care, or standard of care alone . A total of
199 patients underwent randomization with 99 patients receiving the combination
lopinavir–ritonavir and 100 receiving standard of care. The primary endpoint was
time to clinical improvement and was not met in terms of the study. No benefit was
observed since time to clinical improvement was same in both arms (16 days).
Mortality at 28 days was similar in both groups as well as the percentages of patients
with detectable viral RNA at various time points. The authors conclude that the
combination showed no benefit in hospitalized patients with severe COVID-19 illness
and future trials may help to confirm or exclude the clinical benefit of the
combination. The study was not blinded, and this might have affected the
assessment of clinical improvement. The study was also underpowered to highlight
small effects. In another study the efficacy and safety of the combination
lopinavir/ritonavir was assessed in patients with mild/moderate COVID-19 in
comparison to arbidol . Arbidol is an anti-influenza drug targeting the viral
hemagglutinin (HA) and can effectively block the fusion of influenza virus with its host
cell. It has efficiently inhibited SARS-CoV-2 infection in vitro and therefore was used
in the context of a clinical trial against COVID-19. The study was randomized and
enrolled 86 patients with mild/moderate disease, 34 were randomly assigned to
receive LPV/r, 35 to arbidol and 17 received no antiviral medication (control group).
The primary endpoint was the rate of positive-tonegative conversion of SARS-CoV-2
with RT PCR. There were no differences between the two groups both in primary and
secondary endpoints, the rates of antipyresis, cough alleviation, or improvement of
chest CT at days 7 or 14. Lopinavir-ritonavir or arbidol monotherapy failed to improve
the clinical outcomes of hospitalized patients with mild/moderate COVID-19
infection versus supportive care. The study had quite a small sample size and this was
the main limitation. In a small randomized controlled trial held in China, chloroquine
was compared to lopinavir/ritonavir in treating COVID-19 in 22 hospitalized patients,
none of the patients enrolled was critically ill .Among the 22 randomized patients, 10
received chloroquine and 12 received lopinavir/ritonavir. Both agents showed similar
efcacy in terms of negative SARS CoV2 PCR test results at specifc timepoints, CT scan
improvement and days of hospitalization. The main limitations of the trial were the
very small sample size and the participants fairly young age.The NIH Panel for COVID-
19 Treatment Guidelines that have been recently updated recommends against the
use of lopinavir/ritonavir or other HIV protease inhibitors in COVID-19 infection. This
is due to unfavorable pharmacodynamic data and mainly due to the fact that clinical
trials have not demonstrated a clear clinical benefit in patients with COVID 19
.Favilavir/Avifavir or Avigan is an oral antiviral drug approved in Japan for influenza,
also used for Ebola virus infection. In a randomized, open label trial conducted in
China 240 patients were randomized to receive either Favipiravir (116 assessed) or
Arbidol (120 assessed) . Primary endpoint, defined as clinical recovery rate at Day 7,
was not significantly different between the Favipiravir group and the Arbidol group
(62/120) (p=0.1396). There are several ongoing clinical trials evaluating safety and
efcacy of favilavir against other antivirals in China, Japan, Canada and avifavir in
Russia. Darunavir/Cobicistat and Darunavir/Ritonavir have also been tested in a
randomized controlled trial of 30 patients in China which showed that
darunavir/cobicistat was not effective in the treatment of COVID-19. There are no
data from clinical trials that support the use of other HIV protease inhibitors to treat
COVID-19, such as Atazanavir. Instead of administering a single drug, combination of
antivirals with different mechanisms of action may be more effective. The adverse
event profile of these drugs should not be underestimated HCQ/CQ
Currently, HCQ and CQ are among most widely studied antiviral drugs evaluated for
SARS-CoV-2treatment in more than one hundred clinical trials worldwide . Once
completed, the truth regarding the real therapeutic effects of HCQ/CQ might emerge
from the mystery. One clinical trial was conducted in Guangdong China to evaluate
the therapeutic potential of CQ on COVID-19 patients. The results suggested that CQ
could be an effective and available option among current proposed therapies in the
patients with mild/general SARS-CoV-2 infection . In this study, CQ-treated patients
appeared to regain their pulmonary function quicker and get sooner recovery than
those patients treated with other antiviral agents (lopinavir/ritonavir, a protease
inhibitor combination treatment for human immunodeficiency virus (HIV) infection
). Results from another clinical study claimed that both CQ and HCQ could promote
viral RNA negativity and reduce the time to clinical recovery (TTCR) in moderate form
of COVID-19 ; one randomized controlled trial using HCQ for treatment of COVID-19
was conducted in Wuhan China and the results shown that HCQ treatment
meliorated the fever and reduced the cough duration, suggesting that HCQ may be a
potential treatment for critically COVID-19 patients. More importantly, one clinical
study with critical ill COVID-19 patients demonstrated that HCQ even could
significantly reduce death risk without apparent side-effect on COVID-19 patients
.Despite the positive results from the clinical studies as discussed above, more clinical
evidence has challenged the therapeutic efficacy of HCQ/CQ on COVID19 patients
and some of clinical trials are summarized in Table 2. First, there were no significant
differences in clinical symptoms, inflammatory biomarkers, length of hospital stay
and overall mortality between control group and HCQ/CQ group [50-52] while the
administration of HCQ even increased the risk of mortality . Second, highdose CQ
was associated with the incidence of gastrointestinal disorder, cardiovascular
lethality and QTc interval , which will be discussed in details below. There are several
explanations for the ineffectiveness of HCQ/CQ in the treatment of COVID-19
patients. A recent study found that patients with severe COVID-19 had impaired IFN-
I activity, increased T cell apoptosis and inflammatory response, while the regulatory
effect on immune response by HCQ/CQ is not potent enough to inhibit the over-
activation of innate immune system another analysis suggested that the ORF3a of
SARS-CoV-2 could block the fusion between autophagosomes and lysosomes, so
SARS-CoV-2 can survive by escaping lysosome destruction which made the role of
autophagy lysosome more complicated in the living cycle of SARS-CoV-2. Given the
COVID-19 global pandemic, there is an urgent need for effective and available
antiviral therapy and vaccines. Despite the long history of clinical application of HCQ
and CQ in various human diseases, with advantages of inexpensive and easily
accessible, their therapeutic value in treatment of COVID-19 remains questionable.
The mystery or controversy comes from several aspects. First, both CQ and HCQ
could inhibit the transport of SARS-CoV-2 along the endocytic pathway via
neutralizing the pH value of acidic organelles (endosome and lysosome) in host cells,
which have been verified by several in vitro studies. Second, insufficient and
controversial results from SARSCoV-2 animal models, which greatly challenged the
in vivo antiviral effect of HCQ/CQ. Third, most clinical trials failed to prove the efficacy
of HCQ/CQ on COVID-19 patients but discover obvious cardiovascular toxicity and
gastrointestinal responses from various clinical trials. As a result, in June 2020 FDA
revoked its authorization for the emergency use of HCQ/CQ in COVID-19 patients -
covid-19-update-fda-revokes-emergency-use-authorization-chlor oquineand). At
present, there are still numerous clinical trials ongoing around the world using
HCQ/CQ in treatment of COVID-19, either alone or in combination with other
therapeutics. To move forward, there are important challenges for the
scientific community to conduct more work to repurpose these two ancient drugs
in the combat against this deadly COVID-19 pandemic. Specifically, more
mechanistic studies are necessary to fully discover the exact targets of HCQ/CQ on
both SARS-CoV-2 and host cells, to clarify the potential role of autophagy and
lysosome on the process of viral replication. Furthermore, more animal works are
needed to reveal the pharmacokinetic characteristics of HCQ/CQ and understand
the possible reason for the inconsistent effect of these twoin agents between in
vitro and in vivo investigations. Last and most importantly, it will be critically
important to conduct more clinical trials to optimize the clinical application,
including potential combined therapy, to enhance the therapeutic efficacy and to
reduce the adverse effects on patients. Hopefully, all the research work not only
resolve the mystery regarding the therapeutic efficacy of these two drugs in
COVID19, also add more light at the end of tunnel in our fight against COVID-19.
Arbidol
Umifenovir (Arbidol) is an antiviral drug that has been used against some viruses
such as influenza, Ebola, and hepatitis B and C. It inhibits the membrane fusion
process of influenza viruses . Sequence analysis indicated that s short region of the
trimerization domain (S2) of SARS-CoV-2 spike glycoprotein is similar to the
haemagglutinin protein of influenza. On the other hand, arbidol targets influenza
haemagglutinin. Therefore, arbidol blocks the trimerization of SARSCoV-2 spike
protein and inhibits host cell adhesion and entry . Arbidol has shown an inhibitory
effect on SARSCoV-2 at a concentration of 10–30 μM in vitro (Dong et al., 2020).
Huang et al. conducted a systemic review and meta-analysis to evaluate the
efficacy and safety of umifenovir in COVID-19. They showed that umifenovir is safe
and associated with a higher negative rate of PCR on day 14 in COVID-19 patients.
But, there is no supportive evidence for using umifenovir to improve patient
outcomes with COVID 19 . It seems that more clinical investigation is still required
to judge the efficacy of umifenovir against COVID-19. Favipiravir

Favipiravir is a guanine analogue with a pyrazine carboxamide structure that binds

to and inhibits viral RNA dependent RNA polymerase (RdRp). Its antiviral activity is
decreased in the presence of purine nucleosides due to competitive inhibition In
an open-label controlled study in China, favipiravir showed better outcomes in
COVID-19 patients in terms of disease progression and viral clearance, compared
to LopinavirRitonavir therapy .Favipiravir also demonstrated a better recovery
rate and relief time over umifenovir in a superiority RCT in China . Favipiravir is
currently under Phase III controlled, multi-centre clinical trial as a treatment for a
moderate form of COVID-19 in Italy.

Oseltamivir
Oseltamivir, an approved drug for the treatment of influenza, targets the
neuraminidase distributed on the surface of the influenza virus to inhibit its spread
in the human body . A Japanese study reported that early treatment with
oseltamivir has benefit in suspected COVID-19 patients with fever . However, in
another study in Wuhan, China, treatment with oseltamivir did not produce positive
outcomes
Immunomodulatory agents immunomodulatory drugs could be protective at
reducing certain features of SARSCoV-2 and improving recovery. In addition, it is
important to understand if subjects being treated with the immunomodulatory
agents described have a less severe SARS-CoV-2 infection, as they are deemed
some protection from their immunomodulatory treatment, or if they develop
infections similar to non immunocompromised patients. There is a huge unmet
clinical need to advise patients responsibly about whether they should remain on
their immunomodulatory treatment or not in light of Covid-19 infection. In this
article we will discuss potential treatment options for SARS-CoV-2 using
immunomodulatory drugs and at what stage of the condition they may be beneficial.
Viable treatment options during the global coronavirus pandemic are a much-
needed and an intensely active area of research.

Cytokine-Based Therapies

Targeted biologic therapies against specific cytokines have become the treatment of
choice in active rheumatic inflammatory conditions. Over the last few decades,
improved understanding of the immunology of inflammatory diseases, coupled with
the advancement of technologies allowing mass production of biologic therapies,
has transformed the management of conditions including rheumatoid arthritis,
ankylosing spondylitis, and inflammatory bowel disease with cytokine targeted
biologic therapies.
Data from several groups has shown that cytokine levels are elevated in people
hospitalized with SARS-CoV-2 infection, with a rapid release of cytokines such as
IL-1, IL-6, and TNF alpha.. In the context of other concomitant risk factors such as
male gender, increased age, immunocompromise, and obesity , rapid onset of the
cytokine storm requires urgent treatment to prevent multi-organ failure and death.
It has been noted that severity of SARS-CoV-2 and increased deaths have been
associated with several risk factors, including older age ,male gender , black or
minority ethnic origin , obesity , diabetes mellitus , and cardiovascular disease .
Such observations have led to hypotheses that genetic risk factors for cytokine
release syndrome (CRS) or cytokine storm (CS) may be at play. For example,
conditions including Familial Mediterranean Fever (FMF) or TRAPS (Tumor
Necrosis Factor Associated Periodic Fever Syndromes) are known to be more
prevalent in specific ethnic groups, including Mediterranean, Arab, Jewish, Turkish,
Armenian, North African descent with some mutations found in Asian populations.

Such observations, as highlighted above, have led to the concept that therapies
targeted to IL-6, IL-1, and TNF alpha may have a role to play in the post-infection
stage of SARS-CoV-2. In the post-infective stage, an accelerated inflammatory
response sets in, which has important implications for the management of SARS
CoV-2 infection.

IL-6 Cytokine Inhibitors

Biologics targeted to IL-6, such as tocilizumab, a humanized monoclonal antibody

generated to the IL-6 receptor, are licensed for the management of active
rheumatoid arthritis, juvenile idiopathic arthritis, and replasing or refractory giant
cell arteritis (GCA) . They are also licensed for the treatment of cytokine release
syndrome. IL-6 is a key cytokine in the mediation of fever and the acute phase
reponse, including C-reactive protein and ferritin.

Tocilizumab has already been used in the context of severe Covid-19 infection. A
recent retrospective study reported outcomes for 21 patients in China (7).
Tocilizumab has been used in people with severe features of Covid-19, including in
subjects with severe infection, having a respiratory rate ≥ 30 breaths/min, SpO2≤
93% while breathing room air and a PaO2/FiO2≤ 300 mmHg. In this uncontrolled
study, 21 patients with severe or critical Covid-19 pneumonia were treated with
tocilizumab 400 mg intravenously (7). In many of the subjects treated, the fever
returned to normal within a few days, 15 out of 20 lowered their oxygen
requirement and one patient needed no further oxygen therapy. In 19 out of 20
subjects, there was an improvement in Computerized Tomography (CT) scans of
the chest
IL-1 Cytokine Inhibitors

Interleukin-1 is a very active pro-inflammatory cytokine which is released during

inflammatory processes including sepsis and chronic inflammation. It can lower
pain thresholds but also cause sustained tissue damage . Monotherapy using the IL-
1 receptor antagonist, anakinra, is already proven in several autoinflammatory
syndromes including rheumatoid arthritis, hereditary systemic autoinflammatory
diseases such as Familial Mediterranean Fever (FMF), Cryopyrin-associated
periodic syndrome (CAPS), and TNF receptor-associated periodic syndrome
(TRAPS). There are several commercially available inhibitors of IL-1 which are
licensed, including the IL-1 receptor anatonist anakinra, the soluble decoy receptor
rilonacept and the neutralizing monoclonal antibody to IL-1 beta, canakinumab.

IL-1 modulators are often extremely effective in conditions where there are
sustained fevers and a marked systemic inflammatory response. For example, we
recently treated a case of unexplained fevers, weight loss and night sweats, in a
patient with no known infection, who had genetic sequencing that showed a
mutation in intron 4 of the gene for TNF receptor superfamily 1A (TNFRSF1A),
c.473-72 G > A, which demonstrated the diagnosis of tumor necrosis factor
associated periodic fever syndrome (TRAPS) . Our patient underwent treatment
with the IL-1 receptor antagonist anakinra at 100 mg daily subcutaneously and
within 2 days he had symptomatic improvement, suppression of CRP and serum
amyloid A levels began to normalize .
There are centers across the world that are currently using anakinra for CRS and
CS-related features of Covid-19. The importance of release of IL-1 and IL-6 pro
inflammatory cytokine released by lung tissue in response to toll-like receptor
activation during SARS-CoV-2 infection is recognized and are valid treatment
targets .It remains to be seen if there are specific clinical differences in outcome
between IL-1 or IL-6 inhibition in the setting of severe SARS-CoV-2 infection. It
may be that IL-6 inihibitors may be preferred as a single injection that has sustained
effect over a longer period of time, in comparison to IL-1 inhibitors, which since
they are usually given as a daily injection and therefore may require repeated
dosing.

TNF Alpha Cytokine Inhibitors

The advent of biologic therapies targeted at the inhibition of TNFα in the 1990s led
to a step change in the management of many inflammatory conditions for which the
drugs are licensed, including rheumatoid arthritis, ankylosing spondylitis,
psoriatic arthritis, juvenile arthritis, and inflammatory bowel disease. Currently a
wide variety of formulations of TNF inhibitors are used, including fully humanized
biologics targeted to TNFα that include adalimumab, etanercept, and infliximab.
The demonstration that TNFα is a key cytokine that is produced in a wide range of
conditions causing inflammation, both in the acute and chronic phase, has been
borne out by its success as a treatment in a broad range of conditions. In conditions
such as rheumatoid arthritis, blockade of TNFα leads to a subsequent decrease in
IL-1 and IL-6, adhesion molecules and angiogenic factors such as vascular
endothelial growth factor (VEGF). The rationale for the use of TNF inhibitors in
hospitalized patients with SARS-CoV-2 has been proposed .In people with
inflammatory arthritis and inflammatory bowel disease, screening for tuberculosis
(TB) and malignancy are performed and subjects with a history of latent or active
TB are commenced on TB eradication treatment before starting TNF inhibitors. In
addition, people with a cancer history within the previous 5 years are not usually
given TNF inhibitors. Such considerations may be overriden in the acute setting of
infection with Covid-19, but may have long-term consequences and should be
considered in study designs.

Corticosteroids

Corticosteroids have the ability to suppress inflammation by acting on reducing the

activation of several inflammatory mediators produced by the body during infection
and inflammation . Corticosteroids bind to a corticosteroid receptor (CR) and the
complex translocates to the nucleus where it binds to the glucocorticoid response
element (GRE). This complex increases the transcription of a number of
antiinflammatory genes, including those encoding inhibitory (I)- κB, which inhibits
the activation of nuclear factor (NF)-κB, genes encoding cytokines IL-4, IL-10, IL-
13, and TGFβ . The corticosteroid-CR complex inhibits binding of transcription
factors
(AP)-1 and (NF)-κB to their response elements, thereby reducing the production of
pro-inflammatory cytokines IL-1β and TNFα in activated macrophages.
Corticosteroids also increase the synthesis of lipocortin-1, which inhibits the precursor
of eicosanoids, platelet activating factor and phospholipase A2. The multiple
mechanisms of action of glucocorticoids make them effective at suppressing
inflammatory responses at several sites, including the lung tissue, joint, and systemic
inflammation.
Infection with SARS-CoV-2 infection induces destruction within lung cells, which
triggers a local immune response by activation of macrophages and monocytes,
cytokine release and induce T and B cell responses. The innate and adapative
immune response is usually sufficient to clear the virus-induced damage in most
cases. However, in some people an altered immune response occurs, with
development of severe lung and systemic pathology. Due to their effects on multiple
aspects of inflammation, corticosteroids can be used in the early stages of cytokine
storm and macrophage activation syndrome (MAS), when there is an overwhelming
inflammatory response in the body, often in response to an infectious trigger.
Several studies have shown there is a positive effect by corticosteroids in reducing
immunopathological damage .However, other studies have shown that viral RNA
concentrations of SARS-CoV-2 can increase with corticosteroid treatment
compared with placebo . It may be more prudent to use corticosteroids in a peri-
intensive care setting, when subjects may be entering a cytokine storm, rather than
in treating ambulatory patients or those only requiring routine care for their
infection. Indeed initial analysis from the
RECOVERY trial of 2,104 patients randomized to receive dexamethasone 6 mg
once per day fro 10 days (orally or intravenously) has demonstrated a reduction in
28-day mortality in ventilated patients and patients requiring oxygen compared to
those receiving usual care .There was no benefit for patients who did not require
respiratory support. Peer review publication of this data is awaited.
Monoclonal antibodies to SAR-CoV-2
Monoclonal antibodies are laboratory-made proteins that mimic the immune
system’s ability to fight off harmful antigens such as viruses. Sotrovimab is a
monoclonal antibody that is specifically directed against the spike protein of
SARS-CoV-2 and is designed to block the virus’ attachment and entry into
human cells.

Convalescent Plasma
This treatment option refers to transfusion of plasma loaded with antibodies
from individuals after resolution from a specific pathogen. This technique has
been used for decades . Transfusion can offer a short-term, immediate
immunity for individuals. Convalescent plasma can be used prophylactically
and for already infected patients to attenuate clinical severity . Mechanism of
action is through binding of the transfused antibodies to the pathogen,
resulting in cellular cytotoxicity, phagocytosis, or direct neutralization of the
pathogen . Previously, convalescent plasma was used for two coronaviruses,
SARS-CoV and MERS . One large study in Hong Kong involving 80 patients
with SARS-CoV supported early administration of antibodies fo optimal
clinical effect compared to later administration .Limited data from Taiwan
and South Korea showed clinical benefits in severe cases of SARS-CoV and
MERS . Reported dosage varied widely in terms of the amount of plasma
transfused and antibody titer . Limited data on COVID-19 patients from
China illustrated clinical benefits .Pilot study reported clinical improvement
in terms of fever, cough, tightness of breath, and chest pain while no serious
side effects were reported

Bronchodilators/vasodilators
Wheezing has been not indicated as a common symptom of COVID-19 .
Bronchodilators should certainly be administered whenever indicated
but should not be ordered as standard of care.
Nebulizers are associated with aerosolization increasing the risk of
SARSCoV-2 transmission and should be avoided, especially in cases without
an evidencebased beneft . In patients with suspected or documented
COVID19, nebulized bronchodilator therapy using metered dose inhalers
(MDIs) with spacer devices rather than nebulizers should be reserved for
acute bronchospasm such as asthma or exacerbation of chronic obstructive
pulmonary disease [COPD] exacerbation. If nebulized therapy is used,
patients should be in an airborne infection isolation room, and healthcare
workers should use appropriate personal protection equipment (PPE).
According to recent guidelines, aerosol-generating procedures on ICU
patients with COVID-19 should be performed in a negative pressure
room and the healthcare workers performing aerosol procedures should use
ftted respirator masks (N95 respirators, FFP2, or equivalent), (best practice
statement) . Patients with severe hypoxemia may beneft from pulmonary
vasodilators by improving ventilation-perfusion mismatch and decreasing
pulmonary vascular pressure. Pulmonary vasodilators may be, especially
useful for patients
with decompensated or acute pulmonary arterial hypertension . However,
these agents do not reduce mortality in all-cause ARDS and should not be
used instead of proved therapies. There is no evidence supporting the use of
pulmonary vasodilators in COVID-19 patients. A meta-analysis of 13 RCTs
(1243 patients) on inhaled nitric oxide (NO) in non-COVID-19 patients with
ARDS failed to show signifcant efect on mortality (RR 1.04; 95% CI 0.9 to
1.19), and reported increased risk of acute kidney injury (RR 1.59; 95% CI 1.17
to 2.16). Although inhaled nitric oxide resulted in a transient improvement in
oxygenation for the frst 24 h, the positive efect disappeared beyond 24 h .The
most commonly used agents are inhaled nitric oxide gas and aerosolized
epoprostenol, administered by continuous inhalation. Inhaled NO may be
preferred because of less frequent need of flter changes, decreasing exposure
of healthcare workers caring of COVID-19 patients. Inhaled vasodilators
should only be administered through a closed system to reduce
aerosolization. Improvement in oxygenation with inhaled vasodilators is
typically seen within a few hours after Initiation of administration. Inhaled
prostacyclins such as ilioprost have not been tested yet in severe ARDS.
Based on very low quality of evidence, current guidelines suggest initiation
(trial) of inhaled pulmonary vasodilators as a rescue therapy in mechanically
ventilated adults with COVID-19, severe ARDS and hypoxemia, despite
optimizing ventilation and other rescue strategies. In the absence of rapid
improvement in oxygenation the treatment should be de-escalated . Ongoing
trials are under way (NOSARSCOVID; clinicaltrials.gov; NCT04290871) to
provide more evidence on the efect of inhaled NO in severe acute respiratory
syndrome in COVID-19 patients.

Non‑steroidal anti‑inflammatory drugs (NSAIDs)

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely use as painkillers and
antipyretic agents. Although NSAIDs are effective drugs for symptom relief during
the course of viral and bacterial infections, their use has been linked to higher
rates of cardiovascular events [65, 66]. Consequently, short-term administration of
NSAID in respiratory tract infections remains questionable. The first concerns
regarding NSAID use in patients with COVID-19 raised in March 2020 with a study
showing that angiotensin converting enzyme 2 (ACE-2) activity can be increased by
ibuprofen . It is largely known that SARS-CoV-2 binds to target cells through the
angiotensin converting enzyme 2 (ACE-2) receptor which is mainly expressed in
epithelial cells of the respiratory tract, kidney and blood vessels. It has been
hypothesized that increased expression of ACE-2 receptor linked to ibuprofen use
may facilitate SARS-CoV-2 infection and that ACE-2 stimulating drugs such as
NSAIDs may increase the risk of suffering from more severe COVID-19 . NSAIDs use
has been also implicated in delaying the resolution of inflammation by inhibiting
cyclo-oxygenases and is associated with nephrotoxicity, bleedings
and gastrointestinal complications . Although several studies have linked ibuprofen
with negative outcomes during the course of respiratory infections it is possible that
they are subject to a number of biases . Confounding
by disease severity may serve as a potential risk of bias considering that patients
with more severe disease are more likely to use NSAIDs for symptom relief
compared to patients with mild symptoms. Nevertheless some authorities, have
suggested that paracetamol should be considered first-line antipyretic agent, if not
contraindicated, with ibuprofen reserved for individuals who are unable to tolerate
paracetamol until ongoing trials further clarify harms and benefits of NSAIDs in
people with COVID-19 . LIBERATE Trial in COVID-19 (LIBERATE) is an ongoing
randomized phase 4 double blinded controlled trial testing Lipid Ibuprofen Versus
Standard of Care for Acute Hypoxemic Respiratory Failure Due to COVID-19. The
study aims to evaluate the reduction in severity and progression of lung injury with
three doses of lipid ibuprofen in patients with SARS-CoV-2 infections providing
more pragmatic evidence of the role of ibuprofen use in COVID-19.

Mechanical ventilation/high nasal fow/ECMO

Acute hypoxemic respiratory failure is one of the most common clinical
manifestations that determine clinical outcome in COVID-19 patients. Although the
majority of patients with COVID-19 infection have an asymptomatic or mild
respiratory disease, a small but significant proportion of patients present acute
respiratory distress syndrome (ARDS) requiring hospital and/or intensive care unit
(ICU) admission and support with mechanical ventilation .The value of noninvasive
ventilation has not been fully clarified yet, but most COVID-19 centers use (at
least as a trial) high flow nasal cannula (HFNC)/noninvasive positive pressure
ventilation (NIPPV) in mild to moderate ARDS and reserve endotracheal intubation
and mandatory mechanical ventilation for more severe ARDS patients. While there
is a theoretical risk of healthcare personnel and patients contamination by using
HFNC/NIPPV, there are substantial benefits mostly shown from previous meta-
analysis . These meta-analyses have recently demonstrated that HFNC reduces the
rate of intubation compared with conventional oxygen therapy but also compared
with NIPPV in acute hypoxemic respiratory failure. Based on this evidence, the
European Society of Intensive Care Medicine (ESICM) recommends its use in
COVID-19 patients; however, there is strong recommendation of close
monitoring for signs of respiratory status deterioration and early intubation in
a controlled setting, when HNF/NIPPV are applied in COVID-19 patients . The
exact number of patients requiring mechanical ventilation is not clear yet;
Recent observational data published from the Italian COVID-19 experience in
Lombardy region and from New York City have shown that most critical ill
COVID-19 positive patients admitted in ICU required invasive mechanical
ventilation (>80%) and presented a high hospital mortality rate (~50%) .
Mechanical ventilation management includes protective ventilation and recruit
ability studies with lung mechanics assessment. The
latter seems to have a central role in mechanical ventilation strategy as
ARDS phenotypes in COVID19 have certain peculiarities. COVID-19
patients may present with a particular dissociation between the degree of
hypoxemia and loss of lung volume (compliance) and response to positive
end expiratory pressure (PEEP) possibly due to the distinguished pattern of
“endothelitis”, vascular injury and microangiopathy . However, COVID-19
can also induce refractory hypoxemia and/or hypercapnia, despite optimal
management strategy (including muscle relaxation, prone position, and
pulmonary vasodilators) with subsequent remarkable high in-hospital
mortality. In this specifc group of critical ill COVID-19 patients, where there
is no further treatment option, extracorporeal membrane oxygenation
(ECMO) has been considered to have an important role as a rescue therapy
in treatment strategy to increase survival. Results emerging from the ELSO
registry demonstrate that ECMO is feasible and it has been applied with
safety and efcacy in more than 1000
COVID 19 patients with severe refractory ARDS with a remarkable
ICU/hospital discharge rate of more than 50% .
Miscellaneous Agents and Therapies

Angiotensin-Converting Enzyme 2 Receptor

Angiotensin-converting enzyme 2 (ACE2) receptor is regarded as an
important target in the pathogenesis of COVID-19. Studies reveal that
frequently observed comorbidities, including hypertension and diabetes in
patients infected with SARS-CoV-2, are under medication with
angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor
blocker (ARB) [115–118] that result in overexpression of ACE2. It is
speculated that SARSCoVand SARSCoV-2 bind to human cells via
interaction with ACE2 receptors . The opposing physiological actions of ACE
and ACE2 in the renin-angiotensin system are reviewed to determine the
therapeutic efficacy of ACE2 inhibitors or ARBs .In hypertensive patients,
chronic treatment with angiotensin II type 1 receptor (AT1R) antagonists like
losartan, lisinopril, or olmesartan facilitates cardiac and renal ACE2
overexpression according to some in vivo studies . In contrast, SAR viral
RNA following entry into respiratory epithelial cells downregulates the activity
of ACE2, thereby increasing the levels of angiotensin 2. This may potentially
cause severe lung damage . Continued treatment with these drugs may be
essential for the survival to attenuate the cardiac stress of advancing COVID-
19 infection and limit the vasoconstriction and profibrotic effects of
angiotensin 2 in alveolar capillaries.

Ibuprofen
Some of the anti-inflammatory drugs such as ibuprofen, a nonsteroidal
antiinflammatory drug (NSAID), are activators of ACE2 receptors, same as
ACE inhibitors or ARBs. Their usage can lead to increased risk of contracting
COVID-19 . Since fatal lung failure induced by SARS-CoV infections may be
controlled by blocking renin-angiotensin pathway , ibuprofen may not be
harmful. However, there is no strong evidence, suggesting a link between
intake of an NSAID and worsening symptoms due to infection caused by
SARS-CoV-2. The FDA considers ibuprofen and the likes as a potentially
promising therapeutic agent against COVID-19 .
Thiazolidinediones
Studies have demonstrated that thiazolidinedione and its derivatives, which
are type 2 diabetes mellitus drugs, show efficacious effect against pulmonary
disease induced by respiratory syncytial virus (RSV) or H1N1 influenza
infection . But their role as a therapeutic drug against coronavirus is not yet
explored. Interestingly, it is known that thiazolidinediones may have the
potential to upregulate ACE2 receptor, which is identified as a binding target
for SARS-CoV-2 in host cells . However, lack of clinical evidence makes it
uncertain to determine its therapeutic efficacy against coronavirus infections.
Indomethacin Amici et al. have demonstrated that indomethacin, a wellknown
NSAID and a potential cyclooxygenase (COX) inhibitor, exhibits antiviral
activity against SARS-CoV and canine coronavirus (CCoV). In vitro studies
suggest that indomethacin exhibits dose dependent response in Canine A72
cell monolayers infected with CCoV with an IC50 of 5 uM after 24 h of
exposure. Also, remarkable inhibition against SARSCoV-infected Vero cells
by more than 99% at concentrations that were non-toxic for uninfected cells is
also observed. In addition, indomethacin significantly blocks viral RNA
synthesis in dogs infected with CCoV following oral administration of the drug
(1 mg/kg) . This suggests probable efficacy of indomethacin against
SARSCoV-2 .

Colchicine
Colchicine is an anti-inflammatory drug commonly used for gout management
and a variety of other conditions sharing similar pathophysiology. Its
mechanisms of action are related to interfering with migration of neutrophils
to sites of inflammation and blocking the inflammasome complex in both
neutrophils and monocytes, thus reducing IL1beta activation . Colchicine also
has inhibitory effects on macrophages via the inhibition of the NACHT-
LRRPYD-containing protein 3 (NALP3) inflammasome and pore formation
activated by purinergic receptors
P2X7 and P2X2. There may also be beneficial effects on endothelial
function due to colchicine’s antifibrotic activities. Some patients with
COVID19 present with myopathies and colchicine has been shown to reduce
inflammation in the cardiac myocytes . There are several ongoing studies
investigating colchicine for cytokine storm