1. Introduction
The vast majority of countries around the world are going through the
second wave of COVID-19 pandemic, which constitutes an imminent threat
to society, both in terms of human lives’ loss and devastating economic
consequences. Up to December 17th, more than
74,635,000 people have contracted the disease and deaths exceed
1,657,000 (Worldometer, 2020).
Since the beginning of the outbreak, the main features of SARS-CoV-2,
the clinical characteristics of the disease and the role of many
pharmacological treatments have been extensively studied. For instance,
nowadays it is well known that the COVID-19 is a complex disease with
several clinical phases of progression, affecting many organs apart from
the respiratory tract. Specifically, its progression seems to follow
four main stages (Cordon-Cardo et al., 2020). The first one is the phase
during which the SARS-CoV-2 binds to epithelial cells and starts its
replication. This stage occurs in the initial 1-2 days. The main
proteins involved in the cell entry of SARS-CoV-2 are ACE2 receptor and
TMPRSS2 (Fehr and Perlman, 2015; Hoffmann et al., 2020) and the soluble
form of ACE2 receptor could be the target of potential therapeutic
strategies (Scialo et al., 2020). Many patients can be asymptomatic at
this stage and the innate immune response is commonly limited. In the
second stage, the virus migrates down the respiratory tract, leading to
the occurrence of many symptoms, such as fever, cough, shortness of
breath, fatigue, muscle pain, headache, loss of taste or smell, sore
throat, nausea or vomiting, and diarrhoea (Liu et al., 2020b). In this
stage the innate immune response is triggered and an increase in the
level of CXCL10 or other innate response cytokine (the so-called
”cytokine storm”) is observed as well (Wang et al., 2011; Qian et al.,
2013). The third stage, which commonly occur within 1–2 weeks after
symptom onset, is represented by the multi-system inflammation. Given
the seriousness of symptoms (dyspnoea and hypoxia, ground glass
infiltrate and progression to acute respiratory distress syndrome -
ARDS), and possible cardiac, kidney, and liver damage), patients
frequently require hospitalization (Guo et al., 2020a). This is also the
phase in which abnormal coagulation biomarkers can be detected (such as,
elevated D-dimer), representing sub-clinical progression toward stage 4.
Lastly, a generalized hyper-inflammatory state is common in the stage
(Del Valle et al., 2020; Leppkes et al., 2020). Lastly, a number of
patients may reach the most critical and lethal stage (the last one),
which is characterized by endothelial damage, thrombosis, and
multi-organ dysfunction. The elevated levels of von Willebrand factor
and endothelialitis together with hyperinflammation and
hypercoagulability lead to microthrombi formation and systemic
microvascular dysfunction (Nadkarni et al., 2020). On the other hand,
the combinations of the severe respiratory failure and multi-organ
failure, acute neurological disease, venous and arterial thromboembolic
events, contribute to the increase in mortality for patients at this
stage. In figure 1 the main COVID-19 symptoms by organs and tissues are
shown.
The clinical features of COVID-19 and the inter-patients variability in
its progression demonstrate the complexity of this disease but also the
difficulties faced today in the proper choice of pharmacological
treatments and patients’ management. Several clinical trials and
observational studies have been recently carried out worldwide. In the
first wave of COVID-19 pandemic, many drugs have been used in the
different phases of the disease. In fact, last May, we reported an
overview of the benefit/risk profile of pharmacological treatments used
in patients suffering from COVID-19 (Scavone et al., 2020). Considering
new evidence recently acquired on the effect of different
pharmacological treatments in patients with COVID-19, in this paper we
aim to provide an up-to-date overview of medicines, including
antivirals, antinflammatory and immune-modulating drugs, anticoagulants
and other therapies which have been used around the world to treat
COVID-19 and the related evidence in terms of efficacy and safety
profile from interventional and observational clinical studies. Lastly,
an update of vaccines under advanced clinical development is provided as
well.