life Review Efficacy of Different Types of Therapy for COVID-19: A Comprehensive Review Anna Starshinova 1,*, Anna Malkova 2 , Ulia Zinchenko 3 , Dmitry Kudlay 4,5 , Anzhela Glushkova 6, Irina Dovgalyk 3, Piotr Yablonskiy 2,3 and Yehuda Shoenfeld 2,7,8 1 Almazov National Medical Research Centre, Head of the Research Department, 2 Akkuratov Str., 197341 Saint-Petersburg, Russia 2 Medical Department, Saint Petersburg State University, 199034 Saint-Petersburg, Russia; [email protected] (A.M.); [email protected] (P.Y.); [email protected] (Y.S.) 3 St. Petersburg Research Institute of Phthisiopulmonology, 199034 Saint-Petersburg, Russia; [email protected] (U.Z.); [email protected] (I.D.) 4 NRC Institute of Immunology FMBA of Russia, 115478 Moscow, Russia; [email protected] 5 Medical Department, I.M. Sechenov First Moscow State Medical University, 119435 Moscow, Russia 6 V.M. Bekhterev National Research Medical Center for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; [email protected] 7 Ariel University, Kiryat HaMada 3, Ariel 40700, Israel 8 Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 5265601, Israel * Correspondence: [email protected]; Tel.: +7-9052043861 Citation: Starshinova, A.; Malkova, Abstract: A new coronavirus disease (COVID-19) has already affected millions of people in 213 coun- A.; Zinchenko, U.; Kudlay, D.; tries. The possibilities of treatment have been reviewed in recent publications but there are many Glushkova, A.; Dovgalyk, I.; controversial results and conclusions. An analysis of the studies did not reveal a difference in Yablonskiy, P.; Shoenfeld, Y. Efficacy mortality level between people treated with standard therapy, such as antiviral drugs and dexam- of Different Types of Therapy for ethasone, and new antiviral drugs/additional immune therapy. However, most studies describe COVID-19: A Comprehensive Review. clinical improvement and a decrease in mortality among patients with severe and critical conditions, Life 2021, 11, 753. https:// with the early initiation of additional immune therapy. Possible new targets based on viral life cycles doi.org/10.3390/life11080753 were considered. Unfortunately, the data analysis on the efficacy of different medicine and therapy Academic Editors: regimens among patients with COVID-19, showed little success in decreasing the mortality rate Dimitrios Paraskevis, in all treatment methods. Some efficacy has been shown with an immunosuppressive therapy in Maria Yavropoulou and small patient samples, but when a larger number of patients were analyzed the data did not differ Sotirios Tsiodras significantly from the control groups. Received: 5 July 2021 Keywords: coronavirus infection; SARS-CoV-2; COVID-19; antiviral therapy; immune therapy; Accepted: 26 July 2021 cytokines; plasma; intravenous immunoglobulin IgG Published: 27 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- The first novel coronavirus cases were officially recorded in Wuhan, Hubei Province, iations. 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 [5–7]. Copyright: © 2021 by the authors. There is currently no etiological treatment for coronavirus infection, and a standard Licensee MDPI, Basel, Switzerland. therapy is based on the pathogenesis of the disease. According to the pathogenesis estab- This article is an open access article lished by Chinese scientists, the process can be divided into three stages [8]. Coronaviruses distributed under the terms and entering the mucosa of the upper respiratory tract are likely replicated in the cells of the conditions of the Creative Commons Attribution (CC BY) license (https:// ciliary epithelium [9] and cause rhinitis, glossitis, and a cough with possible systemic creativecommons.org/licenses/by/ intoxication, manifested by fever and arthralgia [10]. When overcoming the upper respira- 4.0/). tory tract barriers, the virus enters the lungs, where it binds to the angiotensin converting Life 2021, 11, 753. https://doi.org/10.3390/life11080753 https://www.mdpi.com/journal/life Life 2021, 11, 753 2 of 16 enzyme (ACE) using the receptor-binding domain (RBD) S1 of the subunit of the surface S (spike) protein, which initiates virion endocytosis in the cell [11–13]. From the lungs, the virus enters the systemic circulation known as the viremia phase. During this stage, the virus attacks cells that also express ACE: type 2 pneumocytes in the alveolar epithelium, heart, kidney, gastrointestinal tract cells, macrophages [14–16], as well as the endothelium of arterial and venous vessels, smooth muscle cells in the arteries [17]. The second stage is the acute phase, characterized by organ lesions due to infection. They can be explained by several mechanisms: the direct cytotoxic effect of the virus on cells, immune-mediated complications, vascular complications, and autoimmune side effects [8,18]. The SARS-CoV- 2 virus induces a weak interferon response of types I, II and III and a strong activation of the interleukin IL-1β/IL-6 pathway [19]. In the lungs, infection of type II alveolar epithe- lial cells activates the inflammasome, which induces the production of IL-1β [20]. IL-1β induces the secretion of IL-6 by endothelial cells and vascular smooth muscle cells, which enhance the inflammatory response [21]. In the lungs immune-competent cells infiltrate the tissue and cause an additional alteration due to excessive secretion of proteases and active forms of oxygen [15,22]. The diffuse alteration of alveoli is characterized by the desquamation of alveolar cells, formation of hyaline membranes, development of lung edema and fibrosis [17,23]. It is important to note that the acute phase, characterized by the development of pneumonia, with adequate treatment and normal functioning of the immune system is followed by a stage three recovery. In risk groups (advanced age, the presence of concomitant diseases), the immune system cannot effectively control the course of the diseases. For this reason, serious life-threatening complications such as cytokine storm and massive thrombosis may occur. In such cases, patients end up in a very serious condition and need intensive care [8]. Therefore, existing therapy is aimed at inhibiting viral replication, as the binding to ACE2 and the activity of viral enzymes prevent the vascular and the immune complications from functioning (Figure1). Despite the wide choice of drugs available, doubts about their efficacy, the most optimal prescription time, and patient selection criteria for certain Life 2021, 11, x FOR PEER REVIEW 3 of 18 drugs remain. Figure 1. The targets of drugs used in clinical practice and their influence on pathogenic processes. Abbreviations:Figure 1. ECThe are targetsendothelio ofcytes, drugs PC are pneumocytes, used in clinical NP are neutrophils, practice and and MP are their mac- influence on pathogenic pro- rophages.cesses. Abbreviations: EC are endotheliocytes, PC are pneumocytes, NP are neutrophils, and MP 2.are Results macrophages. and Discussion 2.1. 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 effi- cacy as a preventive monotherapy. Table 1. The results of the studies on the efficacy of antiviral drugs for COVID-19 treatment. Number Comparison Authors and of Observation The Agent Mode of Drug of Efficiency N Year of Patients Time, Days Conclusions Studied Administration with Control Publication /Control (Median) Group (%) Group Mortality 400/100 mg 99/contr Cao B. et al., lоpinаvir/ri 19.2 1 twice a day 14 ol (n = 28 No difference 2020 [24] tonavir vs. days 100) 25.0 lopinavir/ri 200/50 mg 2 Efficacy: Li Y et al., 2020 34 2 tonavir times/day 7–14 21 85.3 vs. 91.4 [25] versus umifenovir days and 200 vs 76.5 Life 2021, 11, 753 3 of 16 The purpose of this review is to analyze the efficacy of antiviral and immunological treatments of COVID-19. 2. Results and Discussion 2.1. Antiviral Therapies According to the presented data (Table1), there is only an insignificant efficacy of hydroxychloroquine sulfate when used in conjunction with azithromycin and a low efficacy as a preventive monotherapy. Table 1. The results of the studies on the efficacy of antiviral drugs for COVID-19 treatment. Authors and Number of Observation Comparison of The Agent Mode of Drug N Year of Patients/Control Time, Days Efficiency with Conclusions Studied Administration Publication Group (Median) Control Group (%) Mortality Cao B. et al., lopinavir/ 400/100 mg twice a 99/control 19.2 No 1 28 2020 [24] ritonavir day 14 days (n = 100) vs. difference 25.0 lopinavir/ 200/50 mg ritonavir 2 times/day 34 versus Li Y et al., umifenovir Efficacy: 2 7–14 days and 35 and control 21 2020 [25] and 85.3 vs. 91.4 vs 76.5 200 mg 3 t/day (n = 17) hydrochloride 7–14 days monohidrate Hydroxychlo- Efficacy: Gautret Ph. 600 mg/ 3 roquine 20/control (n = 16) 14 57.1 et al., 2020 [26] day 10 days sulfate vs. 12.5 600 mg/ hydroxychlor- day 10 days + Gautret P, et al., Efficacy: 4 oquine sulfate 500 mg on 1-st day, 80/no ≥6 2020 [27] 93.0 + azithromycin further 250 mg 2nd–5th day hydroxychlo- 600 mg on 1-st day, Efficacy: Geleris J. et al., 811/control 5 roquine further 22.5 45.8 2020 [28] (n = 565) sulfate 400 mg/day (no data) Grein J. et al., 200 mg on 1-st day, Efficacy: 6 2020 further 100 mg 53/no 19 47.0 (no data) [29] 2nd–10th day remdesivir 200 mg on 1-st day, Efficacy: WangY.