Efficacy of Different Types of Therapy for COVID-19: A Comprehensive Review

A new coronavirus disease (COVID-19) has already affected millions of people in 213 countries. The possibilities of treatment have been reviewed in recent publications but there are many controversial results and conclusions. An analysis of the studies did not reveal a difference in mortality level between people treated with standard therapy, such as antiviral drugs and dexamethasone, and new antiviral drugs/additional immune therapy. However, most studies describe clinical improvement and a decrease in mortality among patients with severe and critical conditions, with the early initiation of additional immune therapy. Possible new targets based on viral life cycles were considered. Unfortunately, the data analysis on the efficacy of different medicine and therapy regimens among patients with COVID-19, showed little success in decreasing the mortality rate in all treatment methods. Some efficacy has been shown with an immunosuppressive therapy in small patient samples, but when a larger number of patients were analyzed the data did not differ significantly from the control groups.


Introduction
The first novel coronavirus cases were officially recorded in Wuhan, Hubei Province, China (PRC) at the end of December 2019 [1,2]. At the end of 2019, the spread of the novel coronavirus caused by the SARS-CoV-2 virus led to the death of patients in 4-22% of cases [3,4], which were associated with severe manifestations of the disease, most often in adults with concomitant pathologies [5][6][7].
There is currently no etiological treatment for coronavirus infection, and a standard therapy is based on the pathogenesis of the disease. According to the pathogenesis established by Chinese scientists, the process can be divided into three stages [8]. Coronaviruses entering the mucosa of the upper respiratory tract are likely replicated in the cells of the ciliary epithelium [9] and cause rhinitis, glossitis, and a cough with possible systemic intoxication, manifested by fever and arthralgia [10]. When overcoming the upper respiratory tract barriers, the virus enters the lungs, where it binds to the angiotensin converting

Antiviral Therapies
According to the presented data (Table 1), there is only an insignificant efficacy of hydroxychloroquine sulfate when used in conjunction with azithromycin and a low efficacy as a preventive monotherapy.  The purpose of this review is to analyze the efficacy of antiviral and immunological treatments of COVID-19.

Antiviral Therapies
According to the presented data (Table 1), there is only an insignificant efficacy of hydroxychloroquine sulfate when used in conjunction with azithromycin and a low efficacy as a preventive monotherapy. A study of the efficacy of remdesivir in conjuction with COVID-19 was carried out in 53 patients with a confirmed SARS-CoV-2 virus carrier based on PCR and respiratory failure (an oxygen saturation of ≤94%/the need for oxygen support) [29]. In 68% of cases, there was an improvement in the oxygen support class, including 17 out of 30 patients who were on mechanical ventilation, and later extubated. The mortality level in the patient group who received invasive ventilation was 18% (6 out of 34) and 5% (1 out of 19) among those who did not need invasive ventilation. Furthermore, in a larger number of patients with COVID-19, another randomized trial was conducted and its findings indicated the results for the treatment of 538 patients and proved the effectiveness of the drug within 15 days of observation, compared with the control group who received a placebo (n = 521). However, the number of deaths in the groups did not significantly differ (7.1% versus 11.9%) [25].
One of the most significant studies with an analysis of a large number of clinical cases was devoted to the efficacy of dexamethasone in COVID-19 treatment [37]. A decrease of 10% in mortality rate was observed among patients with mechanical ventilation (29.3% vs. 41.4%). The analysis of the total mortality rate among COVID-19 patients with dexamethasone was not as significant (22.5% vs. 25.7%).

Immune Therapy
There are several directions that can be taken for the development of immune therapy for coronavirus infection [38]: Monoclonal antibodies against cytokines and their receptors; • Kinase inhibitors; • Polyclonal antibodies by plasma therapy; • Intravenous immunoglobulin IgG (IVIG); • Polypeptide hormone for maturation of T cells.

Monoclonal Antibodies against Cytokines and Their Receptors
According to the pathogenesis of hyperinflammation in COVID-19, the main participants are IL-1β and IL-6; therefore, the focus of clinical research was to study drugs which can block the signaling pathways of these molecules [19].
The results of 15 different studies using drugs to block the signaling pathways of IL-1 beta and IL-6 in patients with COVID-19 of varying levels of severity, are presented in Table 2. We can see that employing the described drugs had a beneficial effect in reducing the severity of the disease; however, in most cases, the summary indicators (survival/mortality) were similar to the control group.  10 Toniati P et al. [48] severe COVID-19 n = 100 8 mg/kg by two consecutive intravenous infusions 12 h apart -Faster de-escalation of the intensity of care It can be assumed that using cytokine inhibitors is the most appropriate way to treat patients with severe disease and hyperinflammation, where extensive organ damage is not evident and mechanical ventilation support is not needed. Other researchers have come to similar conclusions. Tocilizumab has been described as reducing fever and systemic inflammation within 5-7 days, was associated with improved oxygenation rates within 48-72 h, and also delayed the risk of intubation or mortality [54]. Analysis of clinical trials (RCT-TCZ-COVID-19, CORIMUNO-19-TOCI-1, BACC Bay Tocilizumab, and STOP-COVID-19) showed that mortality can be reduced by early medication of tocilizumab [55].

The Kinase Inhibitors
Janus kinase inhibitors (JAK) downregulate the phosphorylation of the signal transducer and transcriptional activator (STAT) of several inflammatory proteins. Blocking the JAK inhibits the activation of the immune system and the development of inflammation (for example, the cellular response to proinflammatory cytokines such as interleukin IL-6) [56,57].
Baricitinib, a Janus kinase (JAK) inhibitor of JAK1 and JAK2 kinases, and Bruton's tyrosine kinase (BTK), a B-cell antigen receptor signaling molecule, are currently being investigated in clinical trials. The data of the studies (n = 4) are shown in Table 3.
According to the analysis of these studies, the use of Janus kinase inhibitors (JAK) was associated with a clinical improvement; however, a reduction in mortality was not achieved. It should be noted that most results were obtained from small numbers of patients with differing degrees of severity which means that, for more accurate results, additional double-controlled studies with stricter inclusion criteria, a larger number of patients, and the presence of comparison groups were needed. According to some studies, IVIG (intravenous immunoglobulin) [62,63] also achieves some efficacy in the treatment of COVID-19. Some information about clinical studies with the use of IVIG are shown in Table 4. The obtained data are insufficient for making accurate conclusions; however, it can be noted that the use of IVIG during early stages of the disease is associated with an improvement in the clinical parameters of patients and the prognosis of the disease.

Convalescent Plasma Transfusion
Plasma transfusion can eradicate pathogens from the circulation and neutralize ferritin and cytokines [65,66]. Convalescent plasma generated a lot of enthusiasm during early days of the COVID-19 pandemic due to its plausible mechanism of action and its easy availability from donors [67]. Information about clinical research, which was carried out by studying the efficacy of plasma convalescents with the new coronavirus infection. is provided in Table 5. The greatest efficacy of the therapy is observed with the early use of plasma (up to 72 h) among patients with a severe level of the disease. A failure response of plasma therapy was noted in a review by Pathak et al. [67].
Perhaps the conflicting results can be explained by the lack of standards and methods for the screening of donor plasma, in search of the presence of binding and neutralizing antibodies to SARS-CoV-2, which could lead to use of plasma with a low level of antibodies [75].

Polypeptide Hormone for Maturation of T Cells
One of the most underexplored fields of research is immunomodulation using thymosin, a polypeptide hormone used for T-cell maturation. Only two clinical trials (ChiCTR-2000029541 and ChiCTR2000029806) used thymosin in combination with a standard therapy [77].
At this moment in time, it is difficult to draw conclusions on the efficacy of the immune therapy of COVID-19. However, most studies describe a clinical improvement and deacrease in mortality among patients in a severe and critical condition with the early initiation of additional immune therapy. These findings are supported by the study by Alessia Alunno et al., according to which none of the many immunomodulators had an impact on the mortality of patients; however, there is currently no final decision regarding the use of tocilizumab [78].
It is necessary to carry out a comparative analysis on the efficacy of each type of immune therapy in order to determine the effectiveness predictive factors for certain categories of patients, depending on the severity of the disease, age, concomitant diseases, and the time since the onset of symptoms.

Possible Therapy Targets for COVID Treatment
The present therapy has some advantages in its metabolic characteristics, dosages used, and potential efficacy, but "broad-spectrum" medicaments and their side effects should not be underestimated. Therefore, the research on new therapeutic targets and drugs continues to be conducted. The therapies that act on the coronavirus can be divided into several categories based on the specific pathways [79]:
Wu C. et al. [80] conducted a virtual screening of ligands based on 21 targets (including two human targets) and selected molecules capable of inhibiting them. Gordon et al. [81] identified two classes of molecules and experimentally demonstrated their antiviral efficacy: inhibitors of protein biogenesis (zotifine, ternatin-4, and PS3061) and ligands of sigma-1 and sigma-2 receptors (haloperidol, PB28, PD-144418 and hydroxychloroquine, which is undergoing clinical trials). The authors noted the importance of the discovery of antiviral activity in sigma-1 and sigma-2 opioid receptor subtype inhibitors. It is possible that these molecules also contribute to the penetration of the virus into the cells, which may explain some neurological symptoms, in particular anosmia, because the olfactory bulb is rich in these proteins. Possible targets and their role in the life cycle of the virus are shown in the Figure 2. • Virulence factors damaging the host's innate immunity, for example: Nsp1, Nsp3c, ORF7a; • The host's specific receptors or enzymes, for example: TMPRSSS2, ACE2.

Conclusions
Unfortunately, the data analysis on the efficacy of different medicines and therapy regimens among patients with COVID-19 showed little success in decreasing the mortality rate through all methods. Some efficacy was shown with immunosuppressive therapy in a small number of patients, but when a larger number of patients was analyzed, the data did not differ significantly from the control groups. Furthermore, initial hopeful results concerning plasma application were ineffective in larger studies. This analysis led us to postulate that there is no evidence for the effective treatment of COVID-19 patients. Despite the presence of a great number of agents and studies conducted, no effective treatment methods were revealed.
Studies on virtual ligand screening and affinity-purification mass spectrometry revealed a wide spectrum of anti-SARS-COV2 molecules, mostly human proteins (opioid like receptors, factors of replication and translation) involved in the virus life cycle, and the molecules that inhibit them.
The most important aspect is the analysis of data on the use of various types of COVID-19 therapy in patients with a severe, critical course of the disease, especially in older age groups.
The analysis showed that, to date, there is no effective antiviral agent for the treatment of COVID-19. According to the previously obtained data, it was demonstrated that the administration of hydroxychloroquine for the treatment and prevention of coronavirus infection is not effective. On the other hand, the use of remdesevir in some patients, including those who were on invasive ventilation, showed an improvement in the course of the disease without a significant effect on mortality.
It was shown that early use of immunosuppressive agents (e.g., tocilizumab, JAK kinase inhibitors, IVIG) may have affected the severity of clinical manifestations, but did not impact mortality.
The first inspiring data on the transfusion of plasma convalescents to patients with COVID-19 were not confirmed. However, subsequent studies of this method with the formation of common standards may improve these results.
The data which demonstrated potential therapeutic targets (mainly from antiviral, antibacterial, and antihypertensive drugs, as well as human proteins involved in the virus life cycle and the molecules that inhibit them) are encouraging, but at the present moment, they are of scientific rather than practical interest.
Thus, according to the results of this analysis, none of the considered methods of COVID-19 therapy showed a significantly positive effect on mortality or a significant effectiveness in comparison with other methods, indicating the need for further research.