key: cord-0948356-24zv2idh authors: Scavone, Cristina; Mascolo, Annamaria; Rafaniello, Concetta; Sportiello, Liberata; Trama, Ugo; Zoccoli, Alice; Bernardi, Francesca Futura; Racagni, Giorgio; Berrino, Liberato; Castaldo, Giuseppe; Coscioni, Enrico; Rossi, Francesco; Capuano, Annalisa title: Therapeutic strategies to fight COVID‐19: Which is the status artis? date: 2021-05-07 journal: Br J Pharmacol DOI: 10.1111/bph.15452 sha: 7a583294de3f8b5ce939e634e74e2ba25f51be7d doc_id: 948356 cord_uid: 24zv2idh COVID‐19 is a complex disease, and many difficulties are faced today especially in the proper choice of pharmacological treatments. The role of antiviral agents for COVID‐19 is still being investigated and evidence for immunomodulatory and anti‐inflammatory drugs is quite conflicting, whereas the use of corticosteroids is supported by robust evidence. The use of heparins in hospitalized critically ill patients is preferred over other anticoagulants. There are conflicting data on the use of convalescent plasma and vitamin D. According to the World Health Organization (WHO), many vaccines are in Phase III clinical trials, and some of them have already received marketing approval in European countries and in the United States. In conclusion, drug repurposing has represented the main approach recently used in the treatment of patients with COVID‐19. At this moment, analysis of efficacy and safety data of drugs and vaccines used in real‐life context is strongly needed. 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 . 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 (Qian et al., 2013; Wang et al., 2011) . The third stage is represented by a multisystem 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 . In this phase, abnormal coagulation biomarkers can be detected and a generalized hyperinflammatory state is common (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 multiorgan dysfunction . The combinations of severe respiratory failure and multiorgan failure, acute neurological disease, and venous and arterial thromboembolic events contribute to the increase in mortality at this stage. In Figure 1 , the main COVID-19 symptoms, in terms of organs and tissues affected, are shown. Recent studies have discussed the role of genetic errors and gene loci, mainly in IFN-mediated antiviral signalling and chemokinemediated/inflammatory signalling, in life-threatening COVID-19 cases (McCoy et al., 2020) as well as the association between autoimmune diseases and COVID-19-related complications (Karaderi et al., 2020) . In addition, multiple variants of SARS-CoV-2 are circulating globally: the variant B.1.1.7 from the United Kingdom; the variant B.1.351 from South Africa that shares some mutations with B.1.1.7; and the variant P.1 from Brazil. All these variants could spread more easily than other variants, which may lead to more cases of (Centers for Disease Control and Prevention [CDC] , 2021). The clinical features of COVID-19 and the interpatient variability in its progression demonstrate the complexity of this disease, but they also explain difficulties faced in the proper choice of pharmacological treatments. Last May, we reported an overview of the benefit/risk F I G U R E 1 The main symptoms related to COVID-19, as related to the organs and tissues affected profile of pharmacological treatments used in patients suffering from COVID-19 . 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, anti-inflammatory and immune-modulating drugs, anticoagulants and other therapies that have been used around the world to treat COVID-19 and related evidence in terms of efficacy profile from interventional and observational clinical studies. Readers should be aware that data from observational studies do not give highly valid data due to their intrinsic limitations, design and chosen pharmacological combinations. Safety warnings recently analysed by regulatory agencies were reported as well. Lastly, an update of vaccines under advanced clinical development is provided. A large number of antiviral agents are currently being evaluated for COVID-19. Figure 2 shows the main drugs evaluated for and their mechanisms of action. Remdesivir is a nucleotide analogue that inhibits the RNAdependent RNA polymerase (RdRp), essential for viral RNA synthesis of MERS-CoV, SARS-CoV and SARS-CoV-2. A randomized, doubleblind, placebo-controlled, multicentre trial, conducted on hospitalized adults with laboratory-confirmed SARS-CoV-2 infection, showed no difference for the time to clinical improvement between the remdesivir and placebo groups . A randomized, open-label trial, evaluating the efficacy of 5 or 10 days of remdesivir treatment compared with the standard care in hospitalized patients with confirmed severe acute respiratory syndrome and moderate COVID-19 pneumonia, showed that patients treated with 10-day course of remdesivir had no statistically significant difference in clinical status compared with standard care. On the contrary, those treated with 5-day course of remdesivir had a statistically significant difference in clinical status, but the difference was defined as uncertain for clinical importance . A double-blind, randomized, placebo-controlled trial (NIAID-ACTT-1) in adults hospitalized for COVID-19 showed that remdesivir was superior to placebo in shortening the time to recovery. Specifically, patients receiving remdesivir had a median recovery time of 10 days compared with 15 days of patients receiving placebo (Beigel et al., 2020) . Finally, a randomized, open-label, Phase III trial on hospitalized patients with severe COVID-19 not requiring mechanical ventilation, which were randomized to receive intravenous remdesivir for 5 or 10 days, showed no difference in terms of clinical status between the two groups (Goldman et al., 2020) . A meta-analysis of these clinical trials showed that the treatment with remdesivir for 10 days increased the recovery rate at Day 14 in severe COVID-19 patients ([RR] = 1.5, 95% ; [CI] 1.33-1.7) and at Day 28 in moderate and severe COVID-19 patients (RR = 1.14, 95% CI 1.06-1.22). Additionally, in all patients, remdesivir decreased the mortality rate at Day 14, but not at Day 28 (Elsawah et al., 2020) . Based on the results of the NIAID-ACTT-1 trial, the European Medicines Agency (EMA) has granted a conditional marketing authorization to remdesivir for the treatment of adults and adolescents from 12 years of age with COVID-19 pneumonia who require supplemental oxygen. Remdesivir is the first medicine that was recommended for COVID-19 in Europe through a rolling review procedure. However, on 20 November 2020, the World Health Organization (WHO) has issued a conditional recommendation against the use of remdesivir in hospitalized patients with COVID-19, regardless of disease severity, as there is no evidence demonstrating an improvement of survival or other outcomes during its use in these patients (WHO, n.d.) . Currently, the Committee for Medicinal Products for Human Use (CHMP) of EMA is evaluating data on mortality at Day 28 derived from the NIAID-ACTT-1 trial. Moreover, the EMA has requested the full Solidarity data in order to assess if any changes are needed to the marketing authorization of remdesivir. In terms of safety, the EMA is also evaluating a signal for kidney toxicity (EMA, n.d.) . Lopinavir/ritonavir is a combination of lopinavir, a protease inhibitor with high specificity for HIV-1 and HIV-2, and ritonavir, an inhibitor of cytochrome P450, in order to increase lopinavir plasma concentration . Proteases play a key role in the viral life cycle because they are responsible for the release of functional viral proteins. Therefore, their inhibition results in the production of immature virus particles (Uzunova et al., 2020) . First results from randomized trials in patients with COVID-19 did not show any benefit for this combination compared with the standard care alone (Cao, Wang, et al., 2020; Li, Xie, et al., 2020) , In addition, the RECOVERY trial showed no reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death for the lopinavir/ritonavir group . A recent meta-analysis showed no difference between the lopinavir/ritonavir combination and the standard of care in terms of progression to more severe state, mortality and virological cure on Days 7-10. Moreover, no difference in efficacy was observed with lopinavir/ritonavir compared with umifenovir or hydroxychloroquine (Bhattacharyya et al., 2020) . Another meta-analysis demonstrated no significant difference in terms of negative PCR results between patients treated with lopinavir/ritonavir and those treated with the standard care . A retrospective study, carried out in non-severe patients with COVID-19, showed no improvement in the prognosis or shortening of clinical course with lopinavir/ritonavir treatment . On the contrary, a retrospective cohort study showed that the combined antiviral therapy (lopinavir/ ritonavir plus umifenovir) is more effective than lopinavir/ritonavir monotherapy . Based on the available evidence, the regular use of lopinavir/ritonavir in the treatment of COVID-19 cannot be supported and further clinical trials are needed. Favipiravir is a drug authorized for the treatment of influenza virus infections in Japan. It is a prodrug converted into the active form able to inhibit the RdRp, essential for viral replication. A randomized clinical trial, comparing the efficacy and safety of favipiravir with that of umifenovir in hospitalized patients with COVID-19, demonstrated a higher efficacy for favipiravir than umifenovir (P = .01). The most commonly reported adverse events were liver enzyme abnormalities, psychiatric disorders, gastrointestinal symptoms and serum uric acid elevations. . An open-label study, evaluating the effects of favipiravir or lopinavir/ritonavir in patients with COVID-19 who were also treated with aerosol inhalation of IFN-α, showed a faster viral clearance and a better chest computed tomography (CT) change for the favipiravir group . On the contrary, the combination of favipiravir and inhaled IFN-β-1b showed no difference for inflammatory biomarkers at hospital discharge and for the overall length of hospital stay when compared with hydroxychloroquine (Khamis et al., 2020) . Another study failed in demonstrating a virological effect and clinical benefits of baloxavir marboxil and favipiravir. Authors concluded that this result could be F I G U R E 2 Main drugs evaluated for treatment of COVID-19 and their probable mechanisms of action determined by the insufficient concentrations of these drugs relative to their antiviral activities (Lou et al., 2020 ). An adaptive, multicentre, Phase II/III clinical trial of favipiravir compared with standard of care in hospitalized patients with moderate COVID-19 pneumonia demonstrated a rapid antiviral response with favipiravir (Ivashchenko et al., 2020) . Based on these preliminary results, the Russian Ministry of Health granted, in May 2020, a fast-track marketing authorization to favipiravir for the treatment of COVID-19 patients. Currently, two clinical trials are ongoing to evaluate the efficacy and safety of favipiravir alone (NCT04336904) or in combination with tocilizumab (NCT04310228) for the treatment of COVID-19. Based on the available evidence, favipiravir is effective in alleviating symptoms and in the clinical improvement of COVID-19 patients, but further studies are needed to prove its benefit in terms of viral clearance, oxygen support requirement and mortality. Darunavir is an inhibitor of dimerization and of the HIV-1 protease, whereas cobicistat is an inhibitor of cytochromes P450 that increases plasma concentrations of darunavir (Deeks, 2018) . At present, there are conflicting in vitro data on the effect of darunavir in inhibiting SARS-CoV-2 viral replication (Alshaeri & Natto, 2020; De Meyer et al., 2020) . Results from a single-centre, randomized and open-label trial of darunavir/cobicistat plus IFN-α-2b, compared with IFN alpha-2b alone, in COVID-19 patients showed no difference in the proportion of negative PCR results at Day 7 between the two groups . Nicolini et al. (2020) reported the results on the real-life use of darunavir/cobicistat in severe COVID-19 patients. Their findings showed that, although well tolerated, this treatment did not reduce mortality in COVID-19. On the contrary, a case-control study showed a lower mortality for darunavir/cobicistat group than the control group (odds ratio [OR] 0.07, 95% CI 0.01-0.52, P = .009) in critically ill patients with SARS-CoV-2 infection . Sofosbuvir and daclatasvir are direct-acting antivirals that represent potential candidates for the treatment of COVID-19. A trial, evaluating the effectiveness of sofosbuvir and daclatasvir compared with ribavirin in patients with severe COVID-19, showed an RR of death of 0.17 (95% CI 0.04-0.73, P = .02) for the sofosbuvir/ daclatasvir group (Eslami et al., 2020) . Similarly, a randomized controlled clinical trial conducted in adults with moderate or severe COVID-19 showed that the group treated with sofosbuvir/daclatasvir plus standard care had a significant reduction of the duration of hospital stay compared with standard care alone . A single-centre, randomized, controlled trial of adults with moderate COVID-19, comparing the treatment with sofosbuvir, daclatasvir and ribavirin to the standard care, demonstrated instead no difference in terms of median duration of hospital stay, number of intensive care unit (ICU) admissions and the number of deaths between groups, but the cumulative incidence of recovery was higher in the sofosbuvir/ daclatasvir/ribavirin group (Abbaspour Kasgari et al., 2020) . Further investigations in larger clinical trials are needed. Nafamostat and camostat mesilate are inhibitors of TMPRSS211, a protease essential for the penetration of coronaviruses into the cell (Mascolo et al., 2020) . First evidence showed a clinical improvement with the use of nafamostat and hydroxychloroquine, or nafamostat and favipiravir in severe COVID-19 patients (Doi et al., 2020; Iwasaka et al., 2020) . Moreover, nafamostat was also effective in three cases of elderly patients with COVID-19 pneumonia. Both drugs are currently being evaluated in different clinical trials (www.clinicaltrials.gov). Ivermectin, a drug used for parasite infestations, has the ability to reduce, in vitro, the viral RNA of SARS-CoV-2. The ICON study, a chart review of hospitalized patients with confirmed COVID-19 treated with or without ivermectin, showed a lower mortality in the ivermectin group, but no difference was found for the extubation rates or length of stay (Rajter et al., 2020) . Another retrospective study conducted in hospitalized patients showed that a single dose of ivermectin (200 μgÁkg À1 ) did not improve clinical and microbiological outcomes of patients with severe COVID-19 (Camprubí et al., 2020) . Preliminary results from a randomized, controlled, Phase III, clinical trials, showed the efficacy of the combination of ivermectin and doxycycline, compared with placebo (NCT04523831). Preliminary results showed that meplazumab compared with the control group was associated with a faster improvement of pneumonia (Bian et al., 2020) . Two clinical trials are ongoing to evaluate the safety and efficacy of meplazumab in patients with COVID-19 (NCT04275245 and NCT04586153). Bamlanivimab is a recombinant, human IgG1 monoclonal antibody directed against the spike protein of SARS-CoV-2. A Phase I study of bamlanivimab in hospitalized patients with COVID-19 was successfully completed (Eli Lilly and Company, n.d.) , and an interim analysis of an ongoing Phase II clinical trial in outpatients with mild or moderate COVID-19 (BLAZE-1) showed that one of three doses of bamlanivimab accelerates the natural decline in viral load over time (Chen, Nirula, et al., 2020) . Based on these results, on 9 November 2020, bamlanivimab was authorized by the FDA for the treatment of mild to moderate COVID-19 in adults and paediatric patients (≥12 years), who are at high risk for progressing to severe or hospitalization. Bamlanivimab is recommended to be administered as soon as possible after a positive COVID-19 test and within 10 days of symptom onset. Currently, bamlanivimab is being evaluated in a Phase III clinical trial assessing the prevention of COVID-19 in residents and staff at long-term care facilities (BLAZE-2 and NCT04497987) and in the National Institutes of Health (NIH)-led ACTIV-2 study in ambulatory COVID-19 patients. In a press release, Lilly (2021) recently announced that bamlanivimab prevented COVID-19 at nursing homes in the BLAZE-2 trial, reducing risk by up to 80% for residents. On 9 February 2021, the FDA issued an emergency use authorization for bamlanivimab and etesevimab, another monoclonal antibody that is specifically directed against the spike protein of SARS-CoV-2, administered together for the treatment of mild to moderate COVID-19 in adults and paediatric patients who are at high risk for progressing to severe COVID-19 (FDA, n.d.-a). Lab of the Fondazione Toscana Life Sciences. This investigational therapy was obtained starting from convalescent plasma. At this moment, researchers found that the antibody is able to bind the spike protein and disable the virus. Thus, this therapy could serve to both prevent and treat COVID-19 (The Florentine, 2020). Regarding monoclonal antibodies' safety profile, allergic and infusion-related reactions-resulting from the activation of the immune system in response to the antibody-were frequently observed. Their symptoms might include flushing, itching, shortness of breath or low BP (Lloyd et al., 2021) . In conclusion, the role of antiviral agents for COVID-19 is still being investigated. Remdesivir is the only one recommended in Europe for COVID-19, but it was also recently questioned for efficacy and safety and is evaluated by the EMA. Regarding monoclonal antibodies, recent evidence suggests that these drugs are effective in patients at early stage of the disease, preventing the progression of COVID-19 and reducing the morbidity and mortality of infection and the frequency of hospitalizations (Cohen, 2021) . The cost of these drugs might represent a challenge for healthcare systems. In the United States, for instance, the doses will be free of charge, even though some patients might have to pay for them. In November 2020, the federal government waived co-payments for the cost of administering the treatment for people covered by Medicare (The New York Times, 2021). Since the beginning of the COVID-19 pandemic, the determining role of inflammatory cytokines in the worsening of clinical conditions has been identified. Indeed, one of the reasons underlying the occurrence of serious symptoms ( Figure 1 ) is represented by the increase in levels of pro-inflammatory cytokines. These mediators are responsible for the so-called cytokine storm that, in turn, induces ARDS, organ failure and sepsis . Many drugs, acting through different mechanisms, are able to block or reduce the effects mediated by the cytokine storm ( Figure 2 ). Tocilizumab is a monoclonal antibody (Figure 2) , authorized for the treatment of many diseases, including rheumatoid arthritis, which is active against IL-6 receptors, one of the key mediators of the inflammatory process (Scott, 2017) . At the beginning of the pandemic, the drug was tested in China to reduce lung complications in 20 patients with severe SARS-CoV-2 infection, being associated with a reduction of oxygen requirement, resolution of CT lesions, normalization of lymphocyte count, reduction of C-reactive protein levels and hospital discharge . A few months ago, many trials evaluating the effects of tocilizumab started in Italy. However, the availability of new evidence from ongoing clinical trials has led to a change of course. Indeed, the study carried out by the Local Health Unit-IRCCS of Reggio Emilia was stopped early, after the enrolment of 126 patients with COVID-19 pneumonia who did not require invasive or semi-invasive mechanical ventilation procedures. The reason for the early conclusion lies in the absence of benefit in treated patients in terms of either worsening (access to the ICU) or survival (Italian Medicines Agency, 2020a). Similarly, the results of the COVACTA trial did not reveal a benefit of tocilizumab over placebo in patients with severe COVID-19 pneumonia. Indeed, no differences in clinical status between patients treated with tocilizumab and placebo were found. In addition, no differences between groups were found regarding the percentage of patients who died by Week 4 and in ventilator-free days (Roche, 2020) . Despite the negative results of demonstrated that tocilizumab is able to reduce the risk of mechanical ventilation in hospitalized COVID-19 patients but not the short-term mortality, at least according to the results of randomized controlled trials. On the contrary, data from observational studies suggested an association between tocilizumab and lower mortality. In terms of safety profile, no higher risk of infections or any other adverse events was found with tocilizumab use (Tleyjeh et al., 2020) . Given the conflicting evidence currently available on the effects of tocilizumab in COVID-19 patients, no firm conclusion can be drawn. We should wait for the results of other studies, such those from the RECOVERY trial (University of Oxford, 2020b). Furthermore, biochemical parameters like serum IL-6 levels and TH17 cells may contribute to select subgroups of COVID-19 patients that would specifically benefit from the treatment with tocilizumab (Cacciapuoti et al., 2020) . Conflicting results were also obtained for sarilumab (Figure 2 Horowitz index (oxygenation expressed by an increased SpO 2 /FiO 2 ratio). A progressive reduction in the serum amyloid A and CRP inflammation parameters was observed, and patients were discharged within 14 days of hospitalization (Benucci et al., 2020) . Another study evaluated the effects of sarilumab in 53 patients with severe COVID-19. Almost 70% of patients were also treated with darunavir/ ritonavir, whereas 94% were received also hydroxychloroquine. Thirty-nine patients were treated in medical wards, whereas 14 in ICU. Among patients who received the drug in the medical wards, at 19-day median follow-up, almost 90% significantly improved. Among patients who received sarilumab in ICU, almost 36% were still alive at the last follow-up. The overall mortality rate was 5.7% (Gremese et al., 2020) . Data from a further retrospective study, which was carried in 15 hospitalized patients, demonstrated that improvements in respiratory parameters were observed in 10 patients after sarilumab administration. Five patients who received sarilumab died (Montesarchio et al., 2020) . Overall, the majority of clinical studies carried out on sarilumab were observational and limited by a low number of patients. In addition, many other drugs were coadministered. Thus, also for this drug, further clinical data are strongly needed. COVID-19. The study results revealed no difference in the incidence of new onset of COVID-19 between participants treated with hydroxychloroquine (11.8%) and those who received placebo (14.3%). Adverse events were more commonly observed with hydroxychloroquine than with placebo, although no serious adverse reactions were reported (Molina et al., 2020) . A further study found no difference in viral load reduction and clinical outcomes between hydroxychloroquine and standard of care . In addition, the results of a randomized, double-blind, placebo-controlled clinical trial (carried out in 491 outpatients at an early stage of found no differences in symptom severity over 14 days between hydroxychloroquine and placebo (relative difference 12%; p = .117) . The results of another randomized study showed that on Day 14, 100% of patients treated with chloroquine were discharged from the hospital, compared with 50% in the lopinavir/ritonavir group. However, it should be underlined that patients in the chloroquine group were younger and they had started the treatment earlier . Lastly, the preliminary results of the SOLIDARITY study seem to suggest that hydroxychloroquine and the combination of lopinavir/ritonavir and IFNbased regimens have little or no effect on mortality at 28 days or on hospital course (WHO, 2020a). Alongside with data on the efficacy profile of chloroquine and hydroxychloroquine, many data on the safety profile of both drugs were collected as well. The EMA drew the attention on risks of serious adverse reactions (including heart rhythm disturbances), highlighting the need for prescribers to closely monitor patients treated with both drugs (EMA, 2020c). In addition, the EMA recommended the use of these medicines only in clinical trials or in national emergency management programmes in hospital- At the beginning of the outbreak, the role of NSAIDs was misjudged due to some concerns that arose from few studies showed that the fatality rate and the ICU admission were significantly lower among patients treated with baricitinib (Cantini, Niccoli, Nannini, et al., 2020) . Based on data currently available, no firm conclusion can be drawn on the effects of baricitinib in COVID-19 patients. In addition, due to a possible increased risk of herpes zoster and simplex infections, a group of Italian researchers suggested that the use of baricitinib should be considered with extreme caution (Favalli et al., 2020) . Ruxolitinib is a JAK1 and JAK2 inhibitor (El Bairi In conclusion, many immunomodulatory and anti-inflammatory drugs have been tested in patients with COVID-19, but today, the evidence is quite conflicting for most of them. In addition, many of the published studies are observational or suffer from many limitations, including the lack of a sample size calculation or control groups and the use of surrogate endpoints (viral load instead of mortality rate). At present, the highest number of concluded clinical studies was found for tocilizumab, hydroxychloroquine and corticosteroids. Among these drugs, only the use of corticosteroids seems to be supported by robust evidence, whereas data related to the efficacy and safety of tocilizumab and hydroxychloroquine are quite conflicting. Therefore, further data from randomized controlled trial or well-designed observational studies are strongly needed. As shown in Figure 1 , among the most serious clinical complications of COVID-19, there is the onset of a coagulopathy that is a cause of death in COVID-19 patients along with respiratory failure (Asakura & Ogawa, 2020) . At the beginning, the state of hyperinflammation and hypercoagulability was identified as disseminated intravascular coagulation (DIC) (Marietta et al., 2020) . However, the pathophysiology of COVID-19-associated DIC is different from the classic one (septic or traumatic DIC) (Asakura & Ogawa, 2020) . In fact, in COVID-19 patients, the most common pattern of coagulopathy is characterized by increased levels of fibrinogen and D-dimer, a mild prolongation of PT/aPTT and a mild thrombocytopenia, which can also be absent in some patient (Atallah et al., 2020 ; American Society of Hematology, 2020b). The exact mechanisms contributing to coagulopathy in COVID-19 patients are not completely understood. In general, inflammation and coagulation are known to be linked by different molecular signals. Pro-inflammatory mediators can stimulate the expression of intravascular tissue factor, leukocyte adhesion molecules and plasminogen activator inhibitor-1 (PAI-1) (Gozzo et al., 2020) . Moreover, inflammation can activate the coagulation cascade by overexpressing thrombin both systemically and locally in the lungs, leading to fibrin deposition and subsequent tissue damage. SARS-CoV-2 could also directly damage vascular endothelial cells through its bond to ACE2, which could represent the first injury triggering the abnormal coagulation . In this context, the generalized hypercoagulable state of COVID-19 patients could be due to the involvement of Type II pneumocytes, the extensive pulmonary microvascular network and the extensive hyperinflammatory state that is similar to the macrophage activation syndrome. Finally, the development of hypoxemia, secondary to ARDS, might also activate the coagulation cascade and could contribute to endothelial dysfunction (Gozzo et al., 2020; McGonagle et al., 2020) . A better understanding of the thromboembolic risk in patients suffering from COVID-19 could help to optimize both diagnostic strategies and pharmacological management Lodigiani et al., 2020) . In this regard, an observational study found that the in-hospital mortality in patients who required mechanical ventilation was lower for those treated with anticoagulants than those not receiving the anticoagulant treatment (Paranjpe et al., 2020) . Undoubtedly, heparins, either unfractionated or in low MW forms (LMWH), used for blocking or limiting the state of hypercoagulability, represent a good therapeutic option in patients with COVID-19. Apart from anticoagulant properties, heparins mitigate the inflammatory state exercising non-anticoagulant mechanisms such as inhibition of heparanase activity, chemokine and cytokine neutralization, interference with leukocyte trafficking, neutralization of extracellular cytotoxic histones and reduction of viral cellular entry (Buijsers et al., 2020) . Therefore, the benefit of using heparins could be related to the ability of blocking both coagulation and inflammation. Accordingly, a retrospective observational study demonstrated that heparins improved the coagulation dysfunction of COVID-19 patients and exerted anti-inflammatory effects by reducing IL-6 and increasing lymphocyte percentage (SHI et al., 2020) . Another observational study found that the treatment with heparin was associated with a lower mortality in hospitalized patients with COVID-19 (Ayerbe et al., 2020) . (Pavoni et al., 2020) . Based on these considerations, a close clinical monitoring and an individual patient evaluation for the risk of thrombosis and bleedings should be applied (Gozzo et al., 2020) . Currently, several different clinical trials are ongoing to evaluate the treatment with heparin in hospitalized patients with COVID-19 (www.clinicaltrials.gov). Aspirin (acetylsalicylic acid), an irreversible platelet inhibitor used for conditions such as myocardial infarction, strokes and preeclampsia in pregnant women, has been investigated in COVID-19 patients. In addition to its anti-inflammatory and anti-thrombotic effects, aspirin has shown a significant antiviral activity against DNA and RNA viruses, including different human coronaviruses (Bianconi et al., 2020) . Moreover, the use of aspirin has been associated with reduced thrombo-inflammation and lower rates of clinical complications and in-hospital mortality in different types of infections (Bianconi et al., 2020) . Observational studies demonstrated some benefit in reducing the risk of ICU mortality, acute lung injury and ARDS (W. Chen et al., 2015; Erlich et al., 2011) , whereas a larger observational study did not demonstrate any difference between aspirin use and ALI . Moreover, a randomized, double-blind, placebo-controlled, randomized clinical trial, conducted on 390 patients, showed that the use of aspirin compared with placebo did not reduce the risk of ARDS (Kor et al., 2016) . First data from a retrospective cohort study of adult patients hospitalized with COVID-19 showed that aspirin was associated with a decreased risk of mechanical ventilation, ICU admission and in-hospital mortality, with no difference for major bleedings between aspirin and nonaspirin users (Chow et al., 2020) . The drug will be tested for its effect In conclusion, the use of heparins in hospitalized critically ill patients is preferred over other anticoagulants because of the shorter half-life and fewer drug-drug interactions, being also the first choice for pregnant women. Convalescent plasma is a mixture of inorganic and organic compounds, water and proteins (including albumin, immunoglobulins, complement, coagulation and antithrombotic factors). Stringent criteria need to be satisfied in order to be a convalescent donor. Specifically, donors should have the following characteristics: aged between 18 and 65 years, absence of infectious symptoms and a negative test for COVID-19 14 days after the recovery (Tiberghien et al., 2020) . The main procedure to obtain plasma is apheresis, which is based on a continuous centrifugation of blood from the donor (Bloch et al., 2020) . who were randomized to receive convalescent plasma in addition to standard treatment (n = 52) or the standard treatment alone (n = 51). According to the study's results, the convalescent plasma therapy was not associated with a statistically significant improvement in time to clinical improvement within 28 days compared with standard treatment alone . Simonovich et al. carried out a randomized controlled trial in 334 hospitalized adult patients with severe COVID-19 pneumonia, who were randomized to receive convalescent plasma (n = 228) or placebo (n = 105) in addition to standard treatment. Authors evaluated the effects of the therapy in terms of changes in patient's clinical status 30 days after the intervention. As in the previous study, no difference in terms of efficacy was found between treatments groups at Day 30. Regarding the safety profile, infusion-related adverse events were detected in 4.8% of patients in the convalescent plasma group and in 1.9% of patients in the placebo group, even though no significant differences were found in the overall incidence of adverse events or serious adverse events (Simonovich et al., 2020) . On the other hand, few small trials or case series reported that the convalescent plasma therapy might be beneficial in COVID-19 patients. For instance, Duan et al. (2020) reported that the administration of 200 ml of convalescent plasma in 10 severe patients led to a significant improvement in clinical symptoms and no severe adverse effects were observed. Lastly, a further case series described the effects of the convalescent plasma therapy in five critically ill patients with COVID-19 and ARDS, who improved after receiving the therapy . Despite their positive results, these studies' findings should be interpreted with caution considering the limited number of patients who were enrolled and the study designs that did not allow making any comparison. In conclusion, based on the conflicting evidence currently available, the use of convalescent plasma needs to be considered as investigational. Intravenous immunoglobulins, which are isolated from the pooled plasma of healthy donors, are used for the treatment of many autoimmune and inflammatory diseases and could represent a good option to improve the prognosis of critical-type patients with COVID-19 Galeotti et al., 2020) . Many studies are currently investigating the effects of vitamin D in COVID-19 patients. This interest derives from the evidence suggesting the role of vitamin D in reducing the risk of cold and acute respiratory infections. Many mechanisms seem to underlie this effect, including the effects of vitamin D on cellular natural immunity and adaptive immunity through the decrease in cytokine storm (this effect was observed on IFN-γ, TNF-α and CD4 + T-cell count (Ali, 2020) . In addition, vitamin D improves the production of antimicrobial peptides in the respiratory epithelium, potentially reducing the risk of local infection, and it seems to interact with ACE2 (Mitchell, 2020 For instance, Sanofi and GSK announced a delay in their adjuvanted recombinant protein-based COVID-19 vaccine programme due to a low immune response in adults aged >49 years, for an insufficient antigen concentration. The pharmaceutical companies state that they will carry out a Phase IIb study with an improved antigen formulation (Sanofi, 2020) . In conclusion, immunization programmes with COVID-19 vaccines have already started around the world. Therefore, preliminary efficacy and safety data from real life will be soon available. In addition, at this moment, evidence suggests that antibodies generated through vaccination with the currently authorized vaccines also recognize SARS-CoV-2 variants (CDC, 2021). The spread of the new COVID-19 was inevitably followed by an intense search for therapies able to counteract severe signs and symptoms of this disease. Today, pharmacological researches are focusing on different drug classes, including antivirals, immunomodulatory and anti-inflammatory agents, anticoagulants and antiplatelet drugs, convalescent plasma and vitamins. Other drugs are currently administered among inpatients and outpatients with COVID-19, such as antibiotics. The use of these drugs is, on many occasions, necessary, given that patients with COVID-19 may also develop bacterial infections, such as pneumonia. Given the absence of a specific drug able to block the replication of SARS-Cov-2, drug repurposing has represented the main approach recently used. This is the case, for example, of antivirals, whose role however is still debated. Also for remdesivir, which is the only drug recommended for COVID-19, some concerns related to its efficacy profile were raised by the WHO based on the results of the openlabel SOLIDARITY trial. Given these concerns, the EMA is currently re-evaluating the drug. Many immunomodulatory and anti-inflammatory drugs have been tested in patients with COVID-19 as well. Based on current evidence and considering the limitations of published clinical studies on these drugs, no firm conclusions can be drawn. Among these drug classes, tocilizumab, hydroxychloroquine and corticosteroids have been extensively studied, even though only the use of corticosteroids seems to be supported by robust evidence, for both outpatients and inpatients requiring supplemental oxygen. In addition, antiinflammatory actions explain the significant role of NSAIDs, mainly ibuprofen and paracetamol, especially in patients suffering from a mild form of COVID-19 (early stage-manageable at home) to solve symptoms like fever and joint and muscle pain. The role of heparins is noteworthy too. Indeed, the administration of these drugs in critically ill patients is crucial in order to reduce the thromboembolic risk, which is one of the most serious consequences of COVID-19. In addition, based on the results of published studies, the role of convalescent plasma and vitamins is still not clear. Therefore, we should wait for results from clinical trials, which are currently ongoing to evaluate the effects of these therapies on mortality, morbidity, prevention and treatment of COVID-19. Other drugs, such as the combination of monoclonal antibodies REGN-COV2, might represent a powerful strategy to avoid patients' hospitalization and alleviate the burden on the healthcare system. At this moment, REGN-COV2 and bamlanivimab have received approval from the FDA, whereas the EMA has started the rolling review for REGN-COV2. The Italian Medicines Agency recently decided to make these treatments available for specific patient populations, while continuing the evaluation of evidence on their efficacy and safety profile. In conclusion, the results of the studies summarized in this review article were quite conflicting. Apart from methodological limitations of clinical studies, there was a large difference in how studies defined clinical endpoints whether that be mortality, negative PCR testing, hospital discharge or safety profile of drugs. In addition, we should consider that few SARS-CoV-2 variants were detected and, at this moment, it is not possible to exclude the possibility that these variants might evade some pharmacological therapies presently effective. Lastly The authors declare no conflicts of interest. Data sharing is not applicable to this article because no new data were created or analysed in this study. 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