- Open Access
An overview on the treatments and prevention against COVID-19
Virology Journal volume 20, Article number: 23 (2023)
The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to plague the world. While COVID-19 is asymptomatic in most individuals, it can cause symptoms like pneumonia, ARDS (acute respiratory distress syndrome), and death in others. Although humans are currently being vaccinated with several COVID-19 candidate vaccines in many countries, however, the world still is relying on hygiene measures, social distancing, and approved drugs.
There are many potential therapeutic agents to pharmacologically fight COVID-19: antiviral molecules, recombinant soluble angiotensin-converting enzyme 2 (ACE2), monoclonal antibodies, vaccines, corticosteroids, interferon therapies, and herbal agents. By an understanding of the SARS-CoV-2 structure and its infection mechanisms, several vaccine candidates are under development and some are currently in various phases of clinical trials.
This review describes potential therapeutic agents, including antiviral agents, biologic agents, anti-inflammatory agents, and herbal agents in the treatment of COVID-19 patients. In addition to reviewing the vaccine candidates that entered phases 4, 3, and 2/3 clinical trials, this review also discusses the various platforms that are used to develop the vaccine COVID-19.
There is a current outbreak of a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is an etiologic agent of coronavirus disease 2019 (COVID-19), which appeared in Wuhan, China, and now spread worldwide [1, 2]. Compared to other members of the Coronaviridae family, such as the SARS-CoV and MERS-CoV (Middle East respiratory syndrome coronavirus), the mortality rate of SARS-CoV-2 is considerably lower; however, it is more transmissible. So far, > 210 million infected cases and > 4.5 million deaths from SARS-CoV-2 infection have been identified. The coronavirus is transmitted commonly by respiratory droplets and can be asymptomatic between 2 and 14 days. This oscillating period makes it notably hard to reach a primary diagnosis and initiate treatment on time. The most frequent signs of COVID-19 are cough, muscle pain, fever, shortness of breathing, sore throat, fatigue, headache, a loss of smell and taste, and dyspnea . The main target of SARS-CoV-2 in patients is the lower respiratory tract. It is noticeable that adults mostly present with a significant reduction in CD8+ and CD4+ T-cells in the primary stages of the disease . Following this decrease, patients suffer from ARDS for approximately 7–10 days after the beginning of the disease because of fast viral replication, the release of a storm of pro-inflammatory cytokines, initiating chemokine responses, and infiltration of inflammatory cells . In addition to ARDS, complications like neurological complications, RNAaemia, and multi-organ failure are reported in these patients . The progression of severe COVID-19 is associated with possible risk factors such as old-aged, diabetic, hypertensive, immunocompromised patients, and patients with primary diseases such as cancer and neurodegenerative diseases [2, 7, 8].
SARS-CoV-2 is a single-stranded RNA beta-coronavirus with positive polarity and helical symmetry of the nucleocapsid. The structure of the SARS-CoV-2 contains four various structural proteins: spike (S), nucleocapsid (N), membrane (M), and envelope (E) (Fig. 1) [9, 10]. Coronaviruses possess the largest genome among RNA viruses (~ 30-kb nucleotides) and contain at least six open reading frames (ORFs). The first ORF encodes a replicase protein and other ORFs encode structural proteins . The spike proteins are directed outwards from the membrane, and two envelope and membrane proteins are placed among the spike proteins. The role of the nucleocapsid proteins is to condense the RNA genome, which seizes the cell protein machinery in the replication cycle of the virus. The S-protein, containing subunits of S1 and S2, has an important function in binding between virus and ACE2 receptor . S1 attaches to ACE2 receptor of the host cell and S2 is activated through host transmembrane protease serine subfamily member 2 (TMPRSS2) that drives membrane fusion . After entering into the cell, SARS-CoV-2 utilizes endogenous cellular machinery of the host for the transcription, replication, and translation of its RNA genome to various viral proteins which are required for reassembling, encapsulating, and exocytosis of newly created virions from the cell (Fig. 2) . Regrettably, there is no standard prevention and treatment against COVID-19 presently. With an understanding of SARS-CoV-2 structure, its infection mechanisms, and the clinical signs of patients, several treatments had been utilized for COVID-19 clinical studies. So far, therapeutic options for COVID-19 can be classified as antiviral agents, biologic agents, anti-inflammatory agents, and herbal agents. Besides the discovered therapeutic agents, vaccines are also in preclinical and clinical trials. This review focuses on the potential treatments that have been employed up to now in treatment of COVID-19 disease.
Antiviral agents are small molecules that act as inhibitors of different steps of the virus life cycle (Fig. 2). In the primary transmission period of SARS-CoV-2, no antiviral agent has been proven to be efficient for COVID-19 disease. With the accumulation of clinical experiences and the deepening of research, types of antiviral agents are considered potential drugs for the infection of COVID-19.
Remdesivir is found to be the most promising antiviral agent among different potential agents tested for the treatment of the disease COVID-19. At first, Remdesivir was developed for the treatment of hepatitis C, and was subsequently repurposed as a therapeutic agent against Ebola and Marburg virus infections before being considered as a treatment for COVID-19. Remdesivir is an adenosine analog, which enters the host cell in the form of a monophosphoramidate prodrug, then metabolized to an analog of adenosine triphosphate. Remdesivir acts by targeting viral RNA-dependent RNA polymerase (RdRp) and prevents the replication of the virus by premature termination of RNA transcription. Remdesivir possesses wide antiviral activity on many virus families such as paramyxoviruses, pneumoviruses, filoviruses, and coronaviruses (e.g., MERS-CoV and SARS-CoV) . M. Wang and colleagues in an in vitro trial showed that Remdesivir potently prevented SARS-CoV-2 with an EC50 value of 1.76 μMol in Vero E6 cells . Treatment with Remdesivir indicated clinical improvement for the first COVID-19 patient in the United States  and then trials have been started to assess its efficacy in hospitalized COVID-19 patients. In a recent study, clinical recovery was seen in 68% of severe COVID-19 patients who were treated with Remdesivir . Several meta-analyses have been conducted to assess the antiviral activities of Remdesivir on COVID-19 patients. Based on obtained results, Remdesivir did not any significant difference in mortality rate in hospitalized adults with COVID-19; however, it can improve the percent recovered, decreases serious injuries, and probably leads to a decline in the rate of mechanical ventilation [19,20,21]. The National Institutes of Health guidelines later recommended that combining Remdesivir with anti-inflammatory drugs such as Tocilizumab, corticosteroids, and Baricitinib, can increase the benefit observed across all endpoints in patients with pneumonia and on oxygen support [22,23,24]. Recently have been indicated that early Remdesivir therapy in patients with active malignancies reduces 28-day in-hospital mortality by 80% .
Favipiravir is a guanine analog that indicated antiviral activity against new or re-emerging influenza, Ebola, and yellow fever. Favipiravir is intracellularly phosphoribosylated to favipiravir-ribofuranosyl-5ʹ-triphosphate, which can function as a substrate of RdRp of RNA viruses . It is found that Favipiravir prevented the SARS-CoV-2 infection with an EC50 of 61.88 μMol in Vero E6 cells . An open-label control trial to investigate the clinical effect of Favipiravir in COVID-19 patients was performed. The results indicated that the Favipiravir arm had a shorter viral clearance median time than the control arm [4 days versus 11] and also had an improvement rate of 91.43% versus 62.22% in chest imaging . A randomized clinical study indicated that Favipiravir had a clinical improvement rate of day 7 and resulted in improved latency to relief for cough and pyrexia than Arbidol .
Ribavirin is a guanosine analog, which possesses antiviral activity on many RNA viruses, including respiratory syncytial virus, hepatitis C virus, and virus hemorrhagic fevers. Ribavirin exerts its antiviral activity through multimodal mechanisms. The antiviral mechanisms of Ribavirin include interference with polymerase, inhibition of nucleotide biosynthesis, interference with RNA capping, and fatal mutagenesis . Ribavirin was selected for COVID-19 patients in combination with Interferon or Ritonavir/Lopinavir in accordance with clinical guidelines in China (http://www.nhc.gov.cn/xcs/zhengcwj/202002/a5d6f7b8c48c451c87dba14889b30147.shtml). It is found that Ribavirin cannot decrease viral RNA when given alone, therefore, it is given in combination with Interferon-α to modulate and increase host immunity . In an in vitro study, was found that a high dose of Ribavirin is needed to reduce viral infection of SARS-CoV-2 . However, Ribavirin possesses a related risk of hemolytic anemia and remarkable hemoglobin decrease, which is dangerous for patients in respiratory distress . In a retrospective cohort trial is indicated that Ribavirin therapy in severe COVID-19 patients isn't related to reduced negative conversion time for SARS-CoV-2 test and also a reduced mortality rate .
IFNs, known as cytokines, activate innate immune response after the virus infection. IFNs-α/β are wide-range antiviral agents that, in addition to activating the innate immune system, inhibit virus replication by interaction with toll-like receptors. IFN-α has no antiviral effect directly, while IFN-β can stimulate protein synthesis with immunomodulatory and antiviral activities. IFN-α/β both indicated antiviral activity against MERS-CoV and SARS-CoV in vitro . Although IFN-α is found to be effective against SARS-CoV, its selectivity index is low than IFN-β. A retrospective cohort study indicated that a combination of INF-α with Ribavirin improved the clinical situation of patients with MERS-CoV . A triple-combination study of IFN-β1b, Ribavirin, and Lopinavir/Ritonavir demonstrated that significant differences were seen in symptoms relief, shorten the viral shedding duration, and hospital stay in the combination group . A recent exploratory study indicated that IFN-α2b alone or in combination with Arbidol decreased the SARS-CoV-2 duration in the upper respiratory tract and parallel decreased the blood levels of inflammatory markers like interleukin-6 and C-reactive protein .
Ritonavir/Lopinavir are protease inhibitors utilized to treat HIV infection. Proteases are vital enzymes in coronavirus's polyprotein processing. Lopinavir as the HIV protease inhibitor can weaken the virus infectivity by inhibiting the formation of matured virus particles. Lopinavir has a short half-life time, therefore, to increase its half-life is used together with Ritonavir. Ritonavir, a cytochrome CYP3A4 inhibitor, inhibits the metabolism of Lopinavir by inhibiting cytochrome P450 and functions as a pharmacokinetic enhancer of Lopinavir . Ritonavir/Lopinavir indicated antiviral effects against MERS-CoV and SARS-CoV-1 by inhibiting 3-chymotrypsin-like protease activity . A randomized, open-label control study with patients with severe COVID-19 showed that no difference was seen in clinical improvement between the two groups treated with Ritonavir/Lopinavir and standard treatment. However, the secondary results of the study exhibited that in Ritonavir/Lopinavir group compared to those in the standard treatment group, patients had a shorter stay in the intensive care unit (ICU) and 28-day mortality was numerically lower in they .
Arbidol is a nonnucleoside antiviral agent that inhibits fusion between lipid envelope of the virus and the cell membrane of a host, thereby preventing virus entry into host cells. In addition, Arbidol can enhance the immune system of the host by inducing the production of INFs and activating the macrophages. It is found that Arbidol has an antiviral effect on a variety of viruses like a respiratory syncytial virus, hepatitis C and B viruses, influenza virus, and adenovirus . A recent in vitro study showed that Arbidol has the ability for the inhibition of the infection of SARS-CoV-2 with EC50 of 4.11 μM . In a retrospective trial by Deng and coworkers revealed that negative conversion rate of SARS-CoV-2 test in days 7 and 14 is significant elevated in patients treated with a combination of Ritonavir/Lopinavir plus oral Arbidol than patients treated with only Ritonavir/Lopinavir. In addition to, combination therapy remarkably improved the chest CT scans in 7-day .
Chloroquine and Hydroxychloroquine (HCQ) act as antimalarial and autoimmune disease drugs. Recently, their function as potential antiviral drugs has been reported. These two drugs are weak bases, which enter cells and accumulate in the endolysosomes and other acidic organelles, thereby elevating endosomal pH and preventing viral fusion into the cell. They also interfere with the terminal glycosylation of receptor ACE2 . In addition, these two drugs can interfere with the proteolytic processing of M protein, resulting in control of the pro-inflammatory cytokines storm that occurs in late-phase COVID-19 patients . The antiviral activity of Chloroquine (EC50 = 1.13 μM) on Vero E6 cells infected with SARS-CoV-2, was indicated in an in vitro study . A recent clinical study of more than 100 patients with COVID-19 revealed that Chloroquine is superior to the control group in decreasing period symptoms, shortening disease period, and promoting coronavirus-negative conversion . A recent in vitro trial indicated that Hydroxychloroquine with EC50 of 0.72 μM is more powerful compared to Chloroquine . An open-label nonrandomized clinical study exhibited that Hydroxychloroquine in combination with Azithromycin can act as an alternative therapeutic approach to treat COVID-19 . It is found that azithromycin enhanced the effectiveness of Hydroxychloroquine in reducing the viral load . However, some clinical studies reported adverse effects, including prolonged QT interval, death, and transfer to intensive care in COVID-19 patients treated with Chloroquine/Hydroxychloroquine and azithromycin [47,48,49,50].
Recombinant soluble ACE2
ACE2, a transmembrane protein, is a carboxypeptidase and part of the renin-angiotensin system (RAS). ACE2 as a regulator of the RAS protects diverse tissues such as the lung by hydrolyzing angiotensin II to angiotensin 1–7 and angiotensin I to angiotensin 1–9. It is highly expressed in lungs, heart, kidneys, and small intestine and acts as the main receptor for SARS-CoV-2. Coronavirus binds to the ACE2 by its spike protein to enter into the host cells. The ACE2 downregulation by virus binding leads to loss of RAS homeostasis which then drives the severity of the disease . A recent study suggested that an excess of soluble ACE2 would neutralize infection of SARS-CoV-2 via binding spike proteins and inhibiting virus-host membrane fusion . Therefore, the utilization of recombinant human ACE2 to neutralize SARS-CoV-2 before it can bind to the membrane-bound ACE2 is explored as a therapeutic option. Recently, the therapeutic potential of human recombinant soluble ACE2 (hrACE2) to prevent primary SARS-CoV-2 infection, has been shown by Monteil et al. . hrACE2 not only inhibits the early entry of SARS-CoV-2 into host cells but also protects COVID-19 patients from severe acute lung failure .
Azithromycin is an antibiotic that exhibits antiviral and immunomodulatory properties, hence considered a potential treatment for COVID-19. Azithromycin acts in the treatment of COVID-19 by several potential mechanisms . (1) Azithromycin binds to the ganglioside-binding site of SARS-CoV-2 spike protein and inhibits the binding of the virus to gangliosides on the host membrane. (2) Azithromycin can impair the endocytosis process and lysosomal protease action by increasing in lysosomal pH (3). Azithromycin suppresses the activation of CD4+ T-cells in lymphocytes. (4) Azithromycin can shift the polarization of alveolar macrophages to their anti-inflammatory phenotype and enhance apoptosis. (5) Azithromycin decreases the generation of pro-inflammatory chemokines and cytokines. (6) Azithromycin may suppress lung fibrosis through its antifibrotic activity in fibroblasts. As mentioned above Azithromycin has mostly been administered with Hydroxychloroquine to treat COVID-19 .
Ivermectin is a broad-spectrum drug with anti-cancer, antiviral, and antimicrobial properties that has been utilized for the treatment of several infectious diseases. Recently, an in vitro study showed that Ivermectin acts as a powerful inhibitor of the SARS-CoV-2 in the Vero/hSLAM cells. In this study, a 5000-fold reduction in virus RNA levels than the control was observed. The speculated mechanism of the antiviral effect of Ivermectin against COVID-19 is the inhibition of importin α/β1 receptor. Importin, the main class of soluble transport receptors, is responsible for transporting viral proteins into the nucleus of the host cell . In 2021, meta-analyses were done on 18 randomized controlled treatment trials. The findings showed that the use of Ivermectin to treat COVID-19 resulted in significant reductions in mortality, time to viral clearance, and time to clinical recovery. Moreover, data obtained from many controlled prophylaxis trials showed significantly decreased risks of contracting COVID-19 with the regular use of Ivermectin. These trials identified Ivermectin as an oral agent effective in all phases of COVID-19 . However, a phase 3, double-blind, randomized, placebo-controlled trial indicated that none of the Ivermectin, Fluvoxamine, and Metformin drugs prevented hypoxemia occurrence, hospitalization, and death related to COVID-19 . In addition, a meta-analysis done on 25 randomized controlled trials in 2022 indicated that Ivermectin doesn't decrease the risk of mortality risk and the risk of mechanical ventilation requirements .
Nitazoxanide, an antiviral prodrug, is metabolized quickly to the active metabolite tizoxanide, this metabolite is safe and free of mutagenic effects. Previously, antiviral activity of Nitazoxanide against coronaviruses has been shown . Wang et al. indicated that Nitazoxanide can suppress SARS-CoV-2 with a 2.12 μM concentration in Vero E6 cells . A review on possible mechanisms of Nitazoxanide for repurposing in COVID-19 showed that it has the ability for blocking the entry of SARS-CoV-2 and inhibit its multiplication, prevent the cytokine storm, and amplify the host's innate antiviral response. Nitazoxanide may also protect the lung and prevent multiple organ failures .
Camostat mesylate, a serine protease inhibitor, is a powerful inhibitor of TMPRSS2 and has been proposed as a potential antiviral agent against SARS-CoV-2. In vivo and in vitro trials have exhibited that Camostat mesylate blocks virus‐cell membrane fusion and therefore the replication of the virus .
Paxlovid is an antiviral drug developed by Pfizer, which was approved by FDA on December 22, 2021, for treating patients with mild to moderate COVID-19. Paxlovid is an oral drug and 3C-like protease inhibitor; its use should be started during the first days of the disease and should be continued every 12 h for 5 days. Paxlovid is composed of the combination of PF-07321332 with ritonavir: PF-07321332 by inhibiting the protease of the SARS-CoV-2 prevents its replication. Ritonavir inhibits the rapid degradation of PF-07321332 in the body and causes PF-07321332 to remain in the body longer [63, 64]. Clinical research has indicated that if Paxlovid is initiated within the first three to five days of the symptoms onset in high-risk patients for the progression of the disease, it has the highest effect and prevents up to 89% of severe illness, hospitalization, and death . The efficacy and safety of Paxlovid for COVID-19 are indicated in a meta-analysis conducted in 2022 . Mutation of SARS-CoV-2 3CLpro led to resistance against Paxlovid .
Biologic agents, including monoclonal antibodies, convalescent plasma (SARS-CoV-2-specific neutralizing antibodies), hyperimmune sera, and exogenous surfactant delivery have attracted many notices during the outbreak of COVID -19 disease.
Monoclonal antibodies (mAbs), because of their exceptional specificity to the virus, and their ability to coordinate the immune defense, are one of the most promising prophylactic and therapeutic tools to fight against viral infections. mAbs uses two pathways to neutralize COVID-19 infections : (1) by targeting surface spike glycoprotein of SARS-CoV-2, (2) through targeting pro-inflammatory cytokines and chemokines involved in the SARS-CoV-2 infection (Fig. 2).
Interleukin-6 (IL-6), a pleiotropic cytokine with a pro-inflammatory activity, is a critical factor for the activation of the signal transduction pathway resulting in cytokine release syndrome (CRS). The cytokine storm and enhanced level of IL-6 in the blood are considered predictive of a fatal outcome in severe COVID-19 patients. IL-6 by binding to transmembrane receptors (mIL-6R) and soluble receptors (sIL-6R) activates the inflammatory response. Tocilizumab, an anti-IL-6R monoclonal antibody, binds to both receptors of IL-6 and effectively prevents the signal transduction pathway of IL-6. A retrospective study indicated that severe COVID-19 patients treated with Tocilizumab experienced clinical improvements, including fast defervescence, improved respiratory function, and discharged from the hospital without important adverse events [5, 69]. Leronlimab is a humanized mAb and a C–C chemokine receptor type 5 (CCR5) antagonist. The CCR5 is located on T regulatory cells, dendritic cells, and macrophages, to mediate chemotaxis in response to its ligands (CCL3, CCL4, and CCL5) . In SARS-CoV infection, macrophages and airway epithelial cells express high levels of chemokine ligand 5 (CCL5). Leronlimab by competitively binding to the CCR5 inhibits CCL5, thereby reducing the downstream release of pro-inflammatory cytokines and inhibiting the migration of T-regulatory cells to the site of infection are occurred . A small study showed that Leronlimab decreases the increased plasma levels of IL-6 and CCL5, and normalized CD4/CD8 ratios in severe COVID-19 patients .
CR3022 is a SARS-CoV receptor-binding domain (RBD)-specific mAb, which can bind to RBD of SARS-CoV-2 spike proteins. This binding can be established because of the lack of overlap between the ACE2 receptor-binding motif and the antibody’s epitope. In contrast to Yuan et al., Tian and colleagues found that CR3022 bound efficiently with SARS-CoV-2 RBD (KD = 6.3 nM), suggesting that CR3022 alone or in combination with other neutralizing antibodies might have the capability to prevent and treat of COVID-19. On the other hand, CR3022 is highly conserved among several coronaviruses and can be effective for COVID-19 treatment alone or in combination with other neutralizing antibodies [73, 74]. LY-CoV555 (Bamlanivimab) is a powerful anti-spike neutralizing mAb that specifically binds with various epitopes on the spike proteins of SARS-CoV-2. LY-CoV555 has been related to a reduction in viral load and frequency of emergency department visits and hospitalizations in COVID-19 outpatients . LY-CoV1404 (bebtelovimab) is a fully human immunoglobulin G1(IgG1) mAb targeting the RBD of SARS-CoV-2 spike proteins. LY-CoV1404 neutralizes all SARS-CoV-2 variants . Casirivimab plus Imdevimab are two human mAbs that bind to non-overlapping epitopes of RBD of SARS-CoV-2 spike protein . Sotrovimab is a mAb that was identified from a SARS-CoV in 2003. This mAb binds to a conserved epitope in the spike protein RBD . Sotrovimab and BRII-196 plus BRII-198 mAb cocktail potently prevent the replication of SARS-CoV-2 and has indicated effectiveness among COVID-19 outpatients for inhibiting disease progression to hospitalization or death .
In a meta-analysis of randomized controlled trials, it was shown that neutralizing mABs can help decrease the risk of hospitalization or emergency department visits in outpatients with COVID‐19 . On August 31, 2021, was suggested that mAb therapy be administered based on a risk-based approach. For example, adolescents over 12 years of age with mild to moderate COVID-19 are at high risk of disease progression and hospitalization. mAbs can be used as post-exposure prophylaxis in those who are at high risk of exposure to COVID-19. After the emergence of the Omicron variant, Casivimab/Imdevimab and Bamlanivimab/Etesevimab became probably ineffectual as post-exposure prophylaxis or treatment .
Regrettably, SARS-CoV-2 has the potential to escape an efficient response, and mAbs capable to control mutating variants must be developed. Mutations that confer resistance to mAbs usually occur in the RBD and N-terminal domain of SARS-CoV-2 S-protein shown by using a recombinant chimeric VSV/SARS-CoV-2 reporter virus . The E484K substitution in the RBD is one of the most frequent mutations to escape mAbs . Recently, this mutation has been indicated to escape mAbs formerly approved for emergency use by the Food and Drug Administration [84, 85]. It seems that a useful solution to suppress the emergence of antibody resistance and increase the efficiency of mAbs in SARS-CoV-2 infection is to use a mixture of mAbs that target distinct epitopes on the RBD [82, 86, 87].
Sotrovimab is a mAb that seems to be fully effective in the treatment of the Omicron variant. Sotrovimab doesn't block the ACE2 but targets “non-receptor-binding motif (RBM)” epitopes that are common among many sarbecoviruses such as SARS-CoV [88, 89]. Therefore, this mAb avoids the likely antigenic “shift” imposed via the Omicron variant . Recently, an ACE2-Fc fusion protein, SI–F019, presented as a novel therapeutic agent against dominant variants including Omicron that not only isn't its neutralization effectiveness not lost but also is indeed strengthened by the mutations of dominant variants .
Convalescent plasma, i.e. immune plasma collected from individuals recovered from the infectious disease, provides immediate passive short-term immunity to susceptible individuals. Convalescent plasma is a type of therapy or ideal post-exposure prophylaxis for COVID-19. The suppression of viremia by immunoglobulins is an explanation for the effectiveness of convalescent plasma therapy (Fig. 2). The use of convalescent plasma as a neutralizing and/or immunomodulatory agent has been previously reported in Influenza, Ebola, MERS, and SARS patients . The success of utilizing convalescent plasma therapy for COVID-19 patients has been reported in several studies. Shen et al. used convalescent plasma containing SARS-CoV-2-specific antibodies to treat 5 seriously ill COVID-19 patients with ARDS. Following receipt of convalescent plasma, the clinical symptoms remarkably improved . In another study, convalescent plasma was transfused into ten severe COVID-19 patients to rescue them. After the transfusion of convalescent plasma, a fast increase in the level of neutralizing antibodies was found. All ten patients presented improved clinical symptoms, including enhanced lymphocyte counts and reduced C-reactive protein. In addition, in 7 patients who had viremia before convalescent plasma transfusion, viral load was not detected . While data are restricted, they suggest clinical advantages in terms of a decrease in viral loads, resolution of the radiological changes, improved survival, and reduced mortality.
Nowadays, the ineffectiveness of convalescent plasma for hospitalized patients with moderate to severe COVID-19 has been proven by several randomized trials [95, 96]. However, convalescent plasma can be useful for early disease when transfused in high-titer to outpatients within 72 h after the onset of symptoms [97, 98].
The therapy with hyperimmune sera is a type of passive immunotherapy that has been used recently as adjunctive therapy to antivirals in European countries affected by COVID-19 . The aim of passive immunization treatment is the enhancement of immune response and the prevention of disease progression . Hyperimmune sera have polyclonal antibodies, predominantly of heterologous immunoglobulin G (IgG), which can be applied to treat viral infections . The use of hyperimmune serum is strongly feasible when vaccines aren't available or aren't entirely accepted by people . The hyperimmune sera have some advantages over COVID-19 convalescent plasma including, easier preservation, an easier administration route, and a smaller reinfusion volume. Moreover, the low cost of hyperimmune serum production and the more diversification of neutralizing antibodies in it makes it preferable to mAbs .
Exogenous surfactant delivery
Due to the binding S protein of SARS-CoV-2 to ACE2 receptor of alveolar type 2 (AT2) lung cells and the lysis of these cells by the virus, it seems reasonable to reduce the synthesis and secrete endogenous surfactant in COVID-19 patients. Therefore, exogenous surfactant delivery can mitigate its activity deficits. The obtained data from the study of Pive et al. indicated that liquid surfactant delivery to patients with severe COVID-19 ARDS is feasible and well-tolerated .
Hyper-inflammation and cytokine storm are recognized as crucial players in the progression of COVID-19 disease toward severe interstitial pneumonia, ARDS, and coagulopathies. Therefore, finding treatments that target both the virus and consequent hyper-inflammation is essential for the effective treatment of the CCVID-19 disease. Corticosteroids, intravenous immunoglobulin (IVIG), Janus kinase (JAK) inhibitors, and Colchicine, are anti-inflammatory treatments used to treat COVID-19.
Systemic corticosteroids are immunosuppressive agents that are used broadly to treat patients with severe viral ARDS. Corticosteroids by using immunosuppressive and anti-inflammatory properties, minimize the injury created by viruses in the body. The anti-inflammatory property of corticosteroids is related to the suppression of pro-inflammatory genes via signal transduction through their steroid receptors. During outbreaks of MERS-CoV and SARS-CoV, systemic corticosteroids have been used. Although, clinical evidence has revealed that corticosteroid therapy delayed the viral clearance in these infections. Similarly, corticosteroids in patients with influenza pneumonia increased secondary infection rates and mortality . The utilization of corticosteroids for COVID-19 infection management is widely discussed. A recent guideline from the WHO doesn't recommend the utilize of corticosteroids if COVID-19 is suspected because they can prevent the generation of important antiviral mediators (especially, type I and III INFs) . Wu C et al. reported that corticosteroid decreases fatality when utilized in COVID-19 patients with ARDS , although several retrospective trials reported enhanced fatality in treated patients with the corticosteroid . Recently, a recovery trial indicated that Dexamethasone decreased mortality in patients who required oxygen treatment with and without invasive mechanical ventilation .
Budesonide is an inhaled corticosteroid with broad anti-inflammatory properties that recommend for chronic respiratory diseases. The inhibitory effect the certain inhaled corticosteroids on viral replication of SARS-CoV-2 have been shown . Also, the expression of the receptors utilized to enter cells is downregulated by these corticosteroids . The efficiency of inhaled budesonide is investigated in outpatients with COVID-19 mild symptoms in two open-label trials. Results showed that initiation of inhaled Budesonide in these patients may decrease the requirement for necessary care or hospitalization and decrease the time for recovery [112, 113].
Immunomodulatory therapy, such as corticosteroids, may result in more frequent or severe secondary bacterial or fungal superinfections in hospitalized patients. In COVID-19 patients with ARDS on invasive mechanical ventilation, a remarkably greater rate of superinfections has been reported [114, 115]. Søvik et al. indicated that whereas Dexamethasone increases survival in severely ill COVID-19 patients, it also appears to enhance the risk of clinically relevant superinfections .
Fluvoxamine is an approved serotonin reuptake inhibitor (SSRI) for the treatment of depression and obsessive–compulsive disorder. The anti-inflammatory effect of Fluvoxamine was found in a murine sepsis model. It binds to the sigma-1 receptor in immune cells, leading to decreased generation of inflammatory cytokines . In addition, Fluvoxamine decreased the expression of the inflammatory gene in an in vitro study of human macrophages and endothelial cells . In 2020, Lenze et al. indicated that Fluvoxamine could prevent clinical deterioration in early-stage COVID-19 outpatients . Furthermore, Hoertel et al. suggested that the utilization of antidepressants, such as SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), may be related to decreased risk of intubation or death in hospitalized patients with COVID-19 . Because the human lung has a high level of serotonin transporter expression , Fluvoxamine may affect the lung function of patients with COVID-19 . In 2021, Seftel and his colleague performed a prospective cohort study of Fluvoxamine in outpatients infected with SARS-CoV-2. They indicated that the incidence of hospitalization was sex in the observation-alone group and zero in the Fluvoxamine-treated group . Therefore, on April 23, 2021, Fluvoxamine was added to the US NIH COVID-19 Guidelines Panel. A meta-analysis done in 2022 indicated that three oral drugs (Fluvoxamine, Molnupiravir, and Paxlovid) were efficient in decreasing hospitalization rates and mortality in COVID-19 patients. In addition, these drugs exhibit well safety because did not enhance adverse events occurrence. Therefore, they possess the potential to be a promising and breakthrough treatment for COVID-19 .
Anakinra, a recombinant interleukin (IL)‐1 receptor antagonist, prevents IL-1α and IL-1β from attaching to IL-1 type I receptors, thereby neutralizing their activity in immune or/and auto-inflammatory processes. Anakinra has a short half-life which enables it to quickly discontinue its action regarding secondary infections or adverse reactions, therefore, making it suitable for critically ill patients . In addition, the inhibition of IL-1 is related to a decrease in the dysfunction of endothelial and the alteration of microvascular, which seems key in COVID-19–related thromboembolic events . Anakinra is an approved treatment for cytokine storm syndromes and hyper-inflammatory conditions, including cytokine release syndrome, macrophage activation syndrome, and Still's disease . Recently, the effectuality of Anakinra in severe COVID-19 patients has been reported in several small studies. In a cohort study, a significant reduction was observed in the requirement for invasive ventilation and the fatality rate in severe COVID-19 patients, who received Anakinra .
Granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors
GM-CSF is a pro-inflammatory cytokine and myelopoietic growth factor that has a key role in a wide range of immune-mediated diseases. The function of GM-CSF as a pro-inflammatory signal promotes macrophages to launch an immune cascade, which eventually leads to the damage of tissue . It is believed that GM-CSF is a critical operator of lung inflammation in severe COVID-19 pneumonia that operates upstream of other chemokines and pro-inflammatory cytokines . Anti-GM-CSF mAbs can decrease inflammation from COVID-19 by repressing this signaling axis upstream and consequently reducing the downstream generation of various pro-inflammatory mediators involved in the pathogenesis of COVID-19 . Otilimab, Namilumab, Lenzilumab, and Gimsilumab by targeting GM-CSF directly and preventing its interaction with cell surface receptors, neutralizing the biological function of GM-CSF [131, 132]. Mavrilimumab by targeting the alpha subunit of the receptor of GM-CSF blocks its intracellular signaling .
Intravenous immunoglobulin (IVIG)
IVIG is a blood-derived product that is prepared from the plasma of healthy donors and is usually utilized as supportive treatment. IVIG contains a pool of polyclonal immunoglobulin G, which is frequently used as an immunotherapeutic molecule to treat different autoimmune and inflammatory diseases. Favorable results of previous works on MERS and SARS suggested the use of IVIG for managing patients with severe COVID-19. The efficacy of IVIG can be enhanced by utilizing IgG antibodies that are collected from recovered COVID-19 patients in the same city or the surrounding region, to enhance the chance of neutralizing SARS-CoV-2 . High-dose IVIG therapy plays a role in modulating immune inflammation and is considered to increase passive immunity. It is still unclear how IVIG helps patients with severe COVID‐19. The decrease in inflammatory mediators after IVIG therapy, have reported in several studies, therefore they suggested that IVIG could target cytokine storm in patients with severe COVID‐19 by complement scavenging, inhibition of effector T helper cells (Th1/17) cells, expansion of regulatory T-cells, and suppression of the activation of innate immune cells . Shi et al. reported that timely initiation of plasma exchange along with IVIG in severe COVID-19 patients can treat them without mechanical ventilation or intensive supportive treatment . Similarly, in other studies, the early utilize of high-dose IVIG in COVID-19 patients was found to be effective in improving the clinical condition, preventing the progression of pulmonary lesions, and reducing the use of mechanical ventilation and the hospitalization period . Therefore, the timing of administration of IVIG is the main factor determining the outcome of IVIG therapy, it should be administered before the initiation of systemic injury.
Janus kinase (JAK) inhibitors
JAK inhibitors are potent inhibitors of the JAK family enzymes that interfere with the JAK-STAT signaling pathway . The JAK/STAT pathway mediates the effect of various molecules such as interleukins, IFNs, and growth factors . JAK inhibitors have dual anti-inflammatory and anti-viral effects in COVID-19. They inhibit the signaling of many pro-inflammatory cytokines involved in the cytokine storm such as IL-6, and also block entry of SARS-CoV-2 to alveolar type 2 alveolar epithelial cells (Fig. 2) . SARS-CoV-2 can enter into the cell through endocytosis and invade the cells. The AP2-associated protein kinase 1 (AAK1), a member of the numb-associated kinase (NAK) family, is a known regulator of clathrin-mediated endocytosis. Baricitinib is a JAK1/2 inhibitor, which utilized in rheumatoid arthritis to prevent the production of pro-inflammatory cytokine. Baricitinib is also a NAK inhibitor with a particularly high affinity for AAK1 that prevents the passage of the virus into cells. Recently, Baricitinib is suggested as a useful cure for pneumonia during COVID-19 by Richardson et al. They reported that Baricitinib on therapeutic dosing can inhibit AAK1 and cyclin G-associated kinase (another regulator of endocytosis of virus) functions . The other inhibitor JAK is Tofacitinib, which inhibits JAK1 and JAK3 selectivity and has functional selectivity for JAK2. The inhibitory action of Tofacitinib on inflammatory cascade pathways may improve advanced, inflammation-driven lung injury in hospitalized COVID-19 patients. Guimarães et al. reported that Tofacitinib caused a lower risk of respiratory failure or death through day 28 than placebo in patients hospitalized with COVID-19 .
Colchicine, an anti-inflammatory and immunomodulatory agent, is approved for gout and familial Mediterranean fever. Recently, Colchicine has obtained attention in the management of some complications of COVID-19 infection. The main mechanism of Colchicine anti-inflammatory action is related to its ability to inhibit activation of Nod‐like receptor protein 3 (NLRP3) inflammasome. NLRP3 inflammasome is a main pathophysiological component in the ARDS development in patients with COVID-19. The inhibition of the NLRP3 inflammasome by Colchicine results in suppressing the activation of caspase-1 and the subsequent release of IL-1β and IL-18 . Several trials have been registered for COVID-19 treatment via conventional therapeutic doses of colchicine (NCT04326790, NCT04328480, NCT04322682, NCT04322565).
Traditional Chinese medicine (TCM) alone or in combination with Western medicine was considered as an alternative treatment strategy to treat COVID-19, based on historical experience and anecdotal evidence of the prevention of H1N1 influenza and SARS. The utilization of TCM in COVID-19 patients in China presents promising outcomes in the improvement of clinical symptoms and the reduction of deterioration, recurrence, and mortality rates. The mechanism of Chinese herbal medicine (CHM) on COVID-19 is multi-component, multi-pathway, and multi-target. The primary mechanisms are direct anti-viral activity, anti-inflammatory action, the regulation of the immune system, and the protection of target organs. Atractylodis Macrocephalae Rhizoma (Baizhu), Fructus forsythia (Lianqiao), Lonicerae Japonicae Flos, Saposhnikoviae Radix (Fangfeng), Glycyrrhizae Radix Et Rhizoma (Gancao), and Astragali Radix (Huangqi) are some CHM that were broadly used during COVID-19 outbreak in China . However, precise clinical trials on large populations of patients COVID-19 are required to confirm the preventive effect of CHM.
Other treatments against SARS-CoV-2 are listed in Table 1. In addition, to further assess the efficacy of drugs on COVID-19, several pre-clinical and clinical studies of different potential treatments have been performed and their results are listed in Table 2. The SARS-CoV-2 clearance, time to clinical improvement, length of stay in the Ward or ICU, need for mechanical ventilation, and mortality of COVID-19 patients have been assessed in these studies. Moreover, the probability of secondary infection, the need for ICU admission, symptoms resolution, and results related to CT-scan in these patients have been studied.
The rapid development of an effective vaccine is an immediate need to protect the global community from the threat of mortality from COVID-19 disease. Since COVID-19 outbreak began, researchers around the world are working to develop a vaccine, so far there are 273 vaccine candidates in preclinical and clinical trials. COVID-19 vaccination, as part of the exit strategy, can provide a return to previous patterns of socializing, schooling, and working. At first, it was recommended that health workers, people in shielding groups, and people over 65 be vaccinated.
Since vaccine-induced immune response can result in disease, vaccine development for SARS-CoV-2 is accompanied by concern. By necessity, vaccine development for emerging infections will need a shorter flow from discovery to deployment, and thus predicting safety in early the process is important. The vaccine-induced immune response can either appear as an acute response to the vaccine itself or as the enhancement of disease after the infection of the virus . It was found that vaccines targeting the RBD, S1, or S2 subunits of SARS-CoV-2 have high protective effects on COVID-19. Therefore, COVID-19 vaccines were designed and developed to weaken or disrupt the interactions of RBD or destabilize the S protein .
The various platforms are being adopted for COVID-19 vaccine development, including DNA, RNA, protein subunits, live attenuated viruses, inactivated viruses, virus-like particles, and non-replicating viral vectors . As SARS-CoV-2 is new and there is a poor understanding of the nature of protective immune responses, it is uncertain that the vaccine development strategy will be successful. Thus, it is crucial to use different strategies and platforms to develop vaccines in parallel. RNA and DNA-based vaccines have several benefits in a pandemic situation. Their first benefit is the rapid development in the laboratory, due to no need for bio reactor culture techniques. The next benefit is the generation of a robust immune response by these two platforms . Before the COVID-19 pandemic, because of the low stability and dubiety surrounding mRNA vaccine formulation, no mRNA vaccine candidate was successfully commercialized . The mRNA delivery into the cytoplasm is essential; thus, different approaches have been utilized such as polyplexes, cationic nano-emulsions (CNEs), and lipid nanoparticles (LNPs) . DNA vaccines are eukaryotic expression plasmid DNA that encodes target antigen protein. The transcription and translation of the antigen after the vaccine is taken up by host cells can produce immune responses in the body and thereby protect the host . Vaccines based on viral vectors are live attenuated vaccines that use modified safe viruses like adenovirus as the vector to express the desired antigen(s). They have long-term stability that elicits effective and potent immune responses. Furthermore, they can be made on a large scale . Live vector vaccine is a combination of the strong immunogenicity of live attenuated vaccine and the safety of subunit vaccine . If the vector vaccine has already been exposed to the target virus, its effectiveness will decrease because of the previously presenting immunity against the vector .
Live attenuated-virus vaccines can be prepared by utilizing a virus with reduced pathogenesis. Although these vaccines stimulate the innate immune system, there is a probability that attenuated vaccine strain is recombined with wild viruses to create a pathogenic strain . Live attenuated-virus vaccine mostly induces mucosal immunity to decrease the virus mucosal infection. Vaccines based on chemically or physically inactivated viruses have few safety concerns and express a broad range of native virus antigens. These vaccines are weak inducers of cytotoxic CD8+ T cells, a suitable property for an efficient COVID-19 vaccine . The ability to trigger the toll-like receptors including TLR 3, TLR 7/8, and TLR 9 is an important advantage of attenuated and inactivated vaccines. Other advantages of these vaccines that make them suitable for vaccination include the induction of excellent B cell response, the preservation of the viral structure, rapid development, and site-directed mutagenesis . Although inactivated vaccines are more stable than attenuated vaccines, the immune memory produced by inactivated vaccines is short-lived, which requires the inoculation of higher doses and the association of the inactivated virus with an adjuvant .
Most protein subunit vaccines have full-length spike protein of SARS-CoV-2 or portions of it that are used to induce neutralizing antibodies . These antibodies inhibit viral genome uncoating and receptor binding. Subunit vaccines mostly induce CD4+ Th cells and are weak activators of CD8+ T-cells responses. The protein subunit vaccines needs to utilize along with adjuvants to enhance their immunogenicity. The safety of subunit vaccines is increased due to the absence of an entire virus, however, the return of toxicity is an important problem in these vaccines .
The array of spike proteins on the surface of virus-like particles crosslinks the receptor of B cells and activates B cells directly, unlike protein subunit vaccines. Also, virus-like particles need an adjuvant and repeated administration, like inactivated viral and protein subunit vaccines . Virus-like particle is not capable of replicating or inducing infection due to the absence of genetic materials and does not need the protection of biosafety and special laboratory settings. Therefore, they are proper and safe models for vaccine design and viral molecular studies .
To date, from 108 candidate vaccines entered into human clinical phases, 8 candidates have been entered into clinical 4 phase, 19 vaccines into 3 phase, and 6 vaccines into phase 2/3.
Pfizer/BioNTech, named BNT162, is an mRNA-based vaccine, which encodes the RBD of the SARS-CoV-2 spike glycoprotein. The RBD antigen expressed by BNT162 is fused to a T4 fibritin-derived ‘foldon’ trimerization domain to enhance the immune response. Pfizer/BioNTech has announced efficacy of 95% . Moderna vaccines, named mRNA-1273 and mRNA-1273.351, are other mRNA-based vaccines that encode for SARS-CoV-2 spike protein. The efficacy of Moderna has been announced 94.5% in the prevention of COVID-19 . Sinovac (CoronaVac) is a vaccine based overall inactivated virus with an aluminum adjuvant. Sinovac vaccine is currently under phase 4 trials. Sinopharm is developing two inactivated vaccines that are under phase 3 and 4 trials. Preliminary results indicated that Sinovac’s SARS-CoV-2 vaccine generates antibodies that neutralize 10 strains of SARS-CoV-2 . Sinopharm is collaborating with Wuhan Institute of Biological Products and Beijing Institute of Biological Products to develop these two vaccines. Sinopharm has now announced an efficacy of 79% . AstraZeneca in collaboration with Oxford University develops a vaccine with an efficacy of 70% to prevent COVID19. AstraZeneca vaccine (ChAdOx1-S (AZD1222)) is currently under phase 4 trials and uses a non-replicating chimpanzee adenovirus to deliver spike protein of SARS-CoV-2 to elicit immune responses. The expressed spike protein on the surface of the virus particle, triggers both T-cell and antibody responses, which may be protective against COVID-19 . Gamaleya, Sputnik V, is a vaccine based on two adenovirus vectors. Sputnik V is currently under phase 3 trials and reportedly shows 92% protection against COVID-19 . To make both CanSino’s (Ad5-nCoV) and Janssen (Ad26.COV2) vaccines (both are currently under phase 4 trials), adenovirus vector-based vaccine platforms are used. Adenoviruses utilized to make these vaccines are inactivated because of the E1 gene deletion and its replacement with the spike gene . Novavax vaccine (NVX-CoV237) consists of prefusion SARS-CoV-2 spike protein, harvested from genetically modified viruses. NVX-CoV237 efficacy is 86% against UK variant and 60% against South African variant  and is currently under phase 3 trials. Recombinant SARS-CoV-2 vaccines (Anhui Zhifei Longcom Biopharmaceutical/Institute of Microbiology, Chinese Academy of Sciences and West China Hospital, Sichuan University), mRNA vaccines of Curevac and ARCoV (Academy of Military Science (AMS), Walvax Biotechnology and Suzhou Abogen Biosciences), inactivated SARS-CoV-2 vaccine (Institute of Medical Biology/Chinese Academy of Medical Sciences), inactivated vaccine QAZCOVID-IN®-COVID-19 (Research Institute for Biological Safety Problems, Rep of Kazakhstan), inactivated SARS-CoV-2 vaccine (Shenzhen Kangtai Biological Products Co., Ltd.), inactivated vaccine of VLA2001 (Valneva, National Institute for Health Research, United Kingdom), nCov DNA vaccine (Zydus Cadila), SARS-CoV-2 vaccine formulation 1 with adjuvant 1, VAT00002 (Sanofi Pasteur /GSK), FINLAY-FR anti-SARS-CoV-2 vaccine (Instituto Finlay de Vacunas), EpiVacCorona vaccine based on peptide antigens (Federal Budgetary Research Institution State Research Center of Virology and Biotechnology "Vector"), whole-virion inactivated SARS-CoV-2 vaccine, BBV152 (Bharat Biotech International Limited), protein subunit vaccine CIGB-66, RBD with aluminum hydroxide as adjuvant (Center for Genetic Engineering and Biotechnology (CIGB)), recombinant protein vaccine of Nanocovax, aluminum as an adjuvant (Nanogen Pharmaceutical Biotechnology), and inactivated vaccine of ERUCOV-VAC (Erciyes University, Turkey), are other candidate vaccines under phase 3 trials. Moreover, two DNA-based vaccines INO-4800 (Inovio Pharmaceuticals) and AG0301-COVID19 (AnGes/Takara Bio/Osaka University), three protein subunit vaccines SCB-2019 + AS03 (Clover Biopharmaceuticals Inc./GSK/Dynavax),UB-612 (COVAXX/United Biomedical Inc), and MF59 adjuvanted SARS-CoV-2 Sclamp vaccine (CSL Ltd. + Seqirus + the University of Queensland), GRAd-COV2 vaccine based on replication-defective Simian Adenovirus (GRAd) encoding S (ReiThera + Leukocare + Univercells), coronavirus-like particle COVID-19 vaccine (Medicago Inc), COVID-19 inactivated vaccine (Shifa Pharmed Industrial Co), and mRNA-based vaccine mRNA-1273.211 (ModernaTX, Inc.) are currently in combining phases 2 and 3 trials. Vaccine candidates are listed in Table 3.
As COVID-19 is a new disease, efforts are being continued to find a suitable treatment for it. To date, the only approved drug with significant efficacy in the clinical cure of patients with COVID-19 is Paxlovid. Therapeutic agents to treat COVID-19 are selected because of their previously documented antiviral activity against MERS and SARS or other virus infections. There is an immediate requirement to obtain a drug or vaccine with an approved efficacy for the treatment or prevention of COVID-19. After the recent announcement of the efficacy of several COVID-19 vaccine candidates in the protection of disease, a comprehensive strategy is now needed to make sure vaccination of the global population in the next steps. Although efficient vaccination and preventative prevention attempts can be crucial, it is not yet clear whether these vaccines can end the COVID-19 pandemic.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Zalpoor H, Akbari A, Nabi-Afjadi M. Ephrin (Eph) receptor and downstream signaling pathways: a promising potential targeted therapy for COVID-19 and associated cancers and diseases. Hum Cell. 2022;35(3):952–4.
Zalpoor H, Rezaei M, Yahyazadeh S, Ganjalikhani-Hakemi M. Flt3-ITD mutated acute myeloid leukemia patients and COVID-19: potential roles of autophagy and HIF-1α in leukemia progression and mortality. Hum Cell. 2022;2022:1–2.
Talaei S, Mellatyar H, Mohammadi S, Panahi Y, Kianpour P, Akbarzadeh A, et al. Nanotechnology and COVID-19: Potential Application for Treatment. EURAS JOURNAL OF HEALTH.1.
Liu J, Liu Y, Xiang P, Pu L, Xiong H, Li C, et al. Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage. J Transl Med. 2020;18:1–12.
Montazersaheb S, Hosseiniyan Khatibi SM, Hejazi MS, Tarhriz V, Farjami A, Ghasemian Sorbeni F, et al. COVID-19 infection: an overview on cytokine storm and related interventions. Virol J. 2022;19(1):1–15.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–9.
Karimian A, Talaei S, Abdolmaleki A, Asadi A, Akram M, Ghanimi HA. The impact of new coronavirus on cancer patients. J Pharm Care. 2021;9(4):209–26.
Zalpoor H, Bakhtiyari M, Liaghat M, Nabi‐Afjadi M, Ganjalikhani‐Hakemi M. Quercetin potential effects against SARS‐CoV‐2 infection and COVID‐19‐associated cancer progression by inhibiting mTOR and hypoxia‐inducible factor‐1α (HIF‐1α). Phytother Res. 2022;36(7):2679–82.
Kandimalla R, John A, Abburi C, Vallamkondu J, Reddy PH. Current status of multiple drug molecules, and vaccines: an update in SARS-CoV-2 therapeutics. Mol Neurobiol. 2020;2020:1–11.
Payandeh Z, Mohammadkhani N, Nabi Afjadi M, Khalili S, Rajabibazl M, Houjaghani Z, et al. The immunology of SARS-CoV-2 infection, the potential antibody based treatments and vaccination strategies. Expert Rev Anti Infect Ther. 2021;19(7):899–910.
Masters PS. The molecular biology of coronaviruses. Adv Virus Res. 2006;66:193–292.
Nabi-Afjadi M, Heydari M, Zalpoor H, Arman I, Sadoughi A, Sahami P, et al. Lectins and lectibodies: potential promising antiviral agents. Cell Mol Biol Lett. 2022;27(1):1–25.
Nabi-Afjadi M, Karami H, Goudarzi K, Alipourfard I, Bahreini E. The effect of vitamin D, magnesium and zinc supplements on interferon signaling pathways and their relationship to control SARS-CoV-2 infection. Clin Mol Allergy. 2021;19(1):1–10.
Adhikari P, Li N, Shin M, Steinmetz NF, Twarock R, Podgornik R, et al. Intra-and intermolecular atomic-scale interactions in the receptor binding domain of SARS-CoV-2 spike protein: implication for ACE2 receptor binding. Phys Chem Chem Phys. 2020;22(33):18272–83.
Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother. 2020. https://doi.org/10.1128/AAC.00399-20.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–71.
Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020. https://doi.org/10.1056/NEJMoa2001191.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020;382(24):2327–36.
Kaka AS, MacDonald R, Greer N, Vela K, Duan-Porter W, Obley A, et al. Major update: remdesivir for adults with COVID-19: a living systematic review and meta-analysis for the American College of Physicians practice points. Ann Intern Med. 2021;174(5):663–72.
Al-Abdouh A, Bizanti A, Barbarawi M, Jabri A, Kumar A, Fashanu OE, et al. Remdesivir for the treatment of COVID-19: a systematic review and meta-analysis of randomized controlled trials. Contemp Clin Trials. 2021;101:106272.
Wilt TJ, Kaka AS, MacDonald R, Greer N, Obley A, Duan-Porter W. Remdesivir for adults with COVID-19: a living systematic review for American college of physicians practice points. Ann Intern Med. 2021;174(2):209–20.
Beckerman R, Gori A, Jeyakumar S, Malin JJ, Paredes R, Povoa P, et al. Remdesivir for the treatment of patients hospitalized with COVID-19 receiving supplemental oxygen: a targeted literature review and meta-analysis. Sci Rep. 2022;12(1):1–11.
Vitiello A, Ferrara F. Perspectives of association Baricitinib/Remdesivir for adults with Covid-19 infection. Mol Biol Rep. 2022;49(1):827–31.
Sarhan RM, Harb HS, Abou Warda AE, Salem-Bekhit MM, Shakeel F, Alzahrani SA, et al. Efficacy of the early treatment with tocilizumab-hydroxychloroquine and tocilizumab-remdesivir in severe COVID-19 Patients. J Infect Public Health. 2022;15(1):116–22.
Jaroszewicz J, Kowalska J, Pawłowska M, Rogalska M, Zarębska-Michaluk D, Rorat M, et al. Remdesivir decreases mortality in COVID-19 patients with active malignancy. Cancers. 2022;14(19):4720.
Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100(2):446–54.
Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering. 2020;6(10):1192–8.
Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. MedRxiv. 2020;91:56.
Khalili JS, Zhu H, Mak NSA, Yan Y, Zhu Y. Novel coronavirus treatment with ribavirin: groundwork for an evaluation concerning COVID-19. J Med Virol. 2020;92(7):740–6.
Weiss RC, Oostrom-Ram T. Inhibitory effects of ribavirin alone or combined with human alpha interferon on feline infectious peritonitis virus replication in vitro. Vet Microbiol. 1989;20(3):255–65.
Omrani AS, Saad MM, Baig K, Bahloul A, Abdul-Matin M, Alaidaroos AY, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14(11):1090–5.
Tong S, Su Y, Yu Y, Wu C, Chen J, Wang S, et al. Ribavirin therapy for severe COVID-19: a retrospective cohort study. Int J Antimicrob Agents. 2020;56(3):106114.
Dongyuan W, Zigang L, Yihui L. An overview of the safety, clinical application and antiviral research of the COVID-19 therapeutics. J Infect Public Health. 2020;13(10):1405–14.
Hung IF-N, Lung K-C, Tso EY-K, Liu R, Chung TW-H, Chu M-Y, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395(10238):1695–704.
Zhou Q, Chen V, Shannon CP, Wei X-S, Xiang X, Wang X, et al. Interferon-α2b treatment for COVID-19. Front Immunol. 2020;11:1061.
Oldfield V, Keating GM, Plosker G. Enfuvirtide: a review of its use in the management of HIV infection. Drugs. 2005;65(8):1139–60.
Chan JF-W, Yao Y, Yeung M-L, Deng W, Bao L, Jia L, et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis. 2015;212(12):1904–13.
Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382(19):1787–99.
Boriskin YS, Pécheur E-I, Polyak SJ. Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection. Virol J. 2006;3(1):1–9.
Wang X, Cao R, Zhang H, Liu J, Xu M, Hu H, et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discov. 2020;6(1):1–5.
Deng L, Li C, Zeng Q, Liu X, Li X, Zhang H, et al. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: a retrospective cohort study. J Infect. 2020;81(1):e1–5.
Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2(1):1–10.
Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020;71(15):732–9.
Goo J, Tian Z, Yang X. Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72–3.
Gautret P, Lagier J-C, Parola P, Meddeb L, Mailhe M, Doudier B, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949.
Gautret P, Lagier J-C, Honoré S, Hoang VT, Colson P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial revisited. Int J Antimicrob Agents. 2021;57(1):106243.
Mitra RL, Greenstein SA, Epstein LM. An algorithm for managing QT prolongation in coronavirus disease 2019 (COVID-19) patients treated with either chloroquine or hydroxychloroquine in conjunction with azithromycin: Possible benefits of intravenous lidocaine. HeartRhythm Case Rep. 2020;6(5):244–8.
Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Medecine et maladies infectieuses. 2020;50(4):384.
Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020. https://doi.org/10.1136/bmj.m1849.
Zequn Z, Yujia W, Dingding Q, Jiangfang L. Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel. Eur J Pharmacol. 2021;893:173813.
Monteil V, Dyczynski M, Lauschke VM, Kwon H, Wirnsberger G, Youhanna S, et al. Human soluble ACE2 improves the effect of remdesivir in SARS-CoV-2 infection. EMBO Mol Med. 2021;13(1):e13426.
Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clin Sci. 2020;134(5):543–5.
Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020;181(4):905-13.e7.
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586–90.
Echeverría-Esnal D, Martin-Ontiyuelo C, Navarrete-Rouco ME, De-Antonio Cuscó M, Ferrández O, Horcajada JP, et al. Azithromycin in the treatment of COVID-19: a review. Expert Rev Anti Infect Ther. 2021;19(2):147–63.
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787.
Kory P, Meduri GU, Varon J, Iglesias J, Marik PE. Review of the emerging evidence demonstrating the efficacy of ivermectin in the prophylaxis and treatment of COVID-19. Am J Ther. 2021;28(3):e299.
Bramante CT, Huling JD, Tignanelli CJ, Buse JB, Liebovitz DM, Nicklas JM, et al. Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N Engl J Med. 2022;387(7):599–610.
Marcolino MS, Meira KC, Guimarães NS, Motta PP, Chagas VS, Kelles SMB, et al. Systematic review and meta-analysis of ivermectin for treatment of COVID-19: evidence beyond the hype. BMC Infect Dis. 2022;22(1):1–25.
Rossignol J-F. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health. 2016;9(3):227–30.
Lokhande AS, Devarajan PV. A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19. Eur J Pharmacol. 2020;891:173748.
Breining P, Frølund AL, Højen JF, Gunst JD, Staerke NB, Saedder E, et al. Camostat mesylate against SARS-CoV-2 and COVID-19—rationale, dosing and safety. Basic Clin Pharmacol Toxicol. 2021;128(2):204–12.
Roberts JA, Duncan A, Cairns KA. Pandora’s box: Paxlovid, prescribing, pharmacists and pandemic. J Pharm Pract Res. 2022;52(1):1.
Marzi M, Vakil MK, Bahmanyar M, Zarenezhad E. Paxlovid: mechanism of action, synthesis, and in silico study. BioMed Res Int. 2022;2022:7341493.
Mahase E. Covid-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports. British Medical Journal Publishing Group; 2021.
Zheng Q, Ma P, Wang M, Chen Y, Zhou M, Ye L, et al. Efficacy and safety of Paxlovid for COVID-19: a meta-analysis. J Infect. 2023;86(1):66–117.
Heilmann E, Costacurta F, Volland A, von Laer D. SARS-CoV-2 3CLpro mutations confer resistance to Paxlovid (nirmatrelvir/ritonavir) in a VSV-based, non-gain-of-function system. BioRxiv. 2022:2022–07.
Taylor PC, Adams AC, Hufford MM, de la Torre I, Winthrop K, Gottlieb RL. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol. 2021;2021:1–12.
Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci. 2020;117(20):10970–5.
Yang B, Fulcher JA, Ahn J, Berro M, Goodman-Meza D, Dhody K, et al. Clinical characteristics and outcomes of COVID-19 patients receiving compassionate use Leronlimab. Clin Infect Dis. 2020;73(11):e4082–9.
Scurci I, Martins E, Hartley O. CCR5: established paradigms and new frontiers for a ‘celebrity’chemokine receptor. Cytokine. 2018;109:81–93.
Agresti N, Lalezari JP, Amodeo PP, Mody K, Mosher SF, Seethamraju H, et al. Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab. J Transl Autoimmunity. 2021;4:100083.
Yuan M, Wu NC, Zhu X, Lee C-CD, So RT, Lv H, et al. A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science. 2020;368(6491):630–3.
Tian X, Li C, Huang A, Xia S, Lu S, Shi Z, et al. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect. 2020;9(1):382–5.
Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med. 2021;384(3):229–37.
Westendorf K, Žentelis S, Wang L, Foster D, Vaillancourt P, Wiggin M, et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. Cell Rep. 2022;39(7):110812.
O’Brien M, Neto E, Chen K, Isa F, Heirman I, Sarkar N, et al. Casirivimab with imdevimab antibody cocktail for COVID-19 prevention: interim results. Top Antiviral Med. 2021;2021:33–4.
Gupta A, Gonzalez-Rojas Y, Juarez E, Casal MC, Moya J, Falci DR, et al. Early Covid-19 treatment with SARS-CoV-2 neutralizing antibody Sotrovimab. medRxiv. 2021;385(21):1941–50.
Tuccori M, Ferraro S, Convertino I, Cappello E, Valdiserra G, Blandizzi C, et al editors. Anti-SARS-CoV-2 neutralizing monoclonal antibodies: clinical pipeline. MAbs. Taylor & Francis; 2020.
Lin WT, Hung SH, Lai CC, Wang CY, Chen CH. The impact of neutralizing monoclonal antibodies on the outcomes of COVID-19 outpatients: a systematic review and meta-analysis of randomized controlled trials. J Med Virol. 2022;94(5):2222–9.
Wolf J, Abzug MJ, Anosike BI, Vora SB, Waghmare A, Sue PK, et al. Updated guidance on use and prioritization of monoclonal antibody therapy for treatment of COVID-19 in adolescents. J Pediatr Infect Dis Soc. 2022;11(5):177–85.
Weisblum Y, Schmidt F, Zhang F, DaSilva J, Poston D, Lorenzi JC, et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. Elife. 2020;9:e61312.
Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science. 2020;369(6506):1014–8.
Ho D, Wang P, Liu L, Iketani S, Luo Y, Guo Y, et al. Increased resistance of SARS-CoV-2 variants B. 1.351 and B. 1.1. 7 to antibody neutralization. 2021.
Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2021;325(7):632–44.
Andreano E, Piccini G, Licastro D, Casalino L, Johnson NV, Paciello I, et al. SARS-CoV-2 escape from a highly neutralizing COVID-19 convalescent plasma. Proc Natl Acad Sci. 2021;118(36):e2103154118.
Greaney AJ, Starr TN, Bloom JD. An antibody-escape estimator for mutations to the SARS-CoV-2 receptor-binding domain. Virus Evolut. 2022;8(1):veac021.
Cameroni E, Bowen JE, Rosen LE, Saliba C, Zepeda SK, Culap K, et al. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. Nature. 2022;602(7898):664–70.
Lempp FA, Soriaga LB, Montiel-Ruiz M, Benigni F, Noack J, Park Y-J, et al. Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies. Nature. 2021;598(7880):342–7.
Nutini A, Zhang J, Sohail A, Arif R, Nofal TA. Forecasting of the efficiency of monoclonal therapy in the treatment of CoViD-19 induced by the Omicron variant of SARS-CoV2. Results Phys. 2022;35:105300.
Tsai T-I, Khalili JS, Gilchrist M, Waight AB, Cohen D, Zhuo S, et al. ACE2-Fc fusion protein overcomes viral escape by potently neutralizing SARS-CoV-2 variants of concern. Antiviral Res. 2022;199:105271.
Casadevall A, Pirofski L. The convalescent sera option for containing COVID-19. J Clin Investig. 2020;130(4):1545–8.
Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020;323(16):1582–9.
Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci. 2020;117(17):9490–6.
Sekine L, Arns B, Fabro BR, Cipolatt MM, Machado RR, Durigon EL, et al. Convalescent plasma for COVID-19 in hospitalised patients: an open-label, randomised clinical trial. Eur Respir J. 2022. https://doi.org/10.1183/13993003.01471-2021.
Troxel AB, Petkova E, Goldfeld K, Liu M, Tarpey T, Wu Y, et al. Association of convalescent plasma treatment with clinical status in patients hospitalized with COVID-19: a meta-analysis. JAMA Netw Open. 2022;5(1):e2147331-e.
Tobian AA, Cohn CS, Shaz BH. COVID-19 convalescent plasma. Blood J Am Soc Hematol. 2022;140(3):196–207.
Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, et al. Early outpatient treatment for Covid-19 with convalescent plasma. N Engl J Med. 2022;386(18):1700–11.
Kazatchkine MD, Goldman M, Vincent J-L. Antibody-based therapies for COVID-19: can Europe move faster? PLoS Med. 2020;17(5):e1003127.
Gasparyan AY, Misra DP, Yessirkepov M, Zimba O. Perspectives of immune therapy in coronavirus disease 2019. J Korean Med Sci. 2020;35(18):1–9.
da Costa CB, Martins FJ, da Cunha LE, Ratcliffe NA, de Paula RC, Castro HC. COVID-19 and Hyperimmune sera: a feasible plan B to fight against coronavirus. Int Immunopharmacol. 2021;90:107220.
Martins F, Ratcliffe N, Cisne de Paula R, Castro H. COVID-19 and Hyperimmune sera: a feasible plan B to fight against coronavirus. Int Immunopharmacol. 2020;90:107220.
Focosi D, Tuccori M, Franchini M. The road towards polyclonal anti-SARS-CoV-2 immunoglobulins (hyperimmune serum) for passive immunization in COVID-19. Life. 2021;11(2):144.
Piva S, DiBlasi RM, Slee AE, Jobe AH, Roccaro AM, Filippini M, et al. Surfactant therapy for COVID-19 related ARDS: a retrospective case–control pilot study. Respir Res. 2021;22(1):1–8.
Zhou Y, Fu X, Liu X, Huang C, Tian G, Ding C, et al. Use of corticosteroids in influenza-associated acute respiratory distress syndrome and severe pneumonia: a systemic review and meta-analysis. Sci Rep. 2020;10(1):1–10.
Kumar K, Hinks TS, Singanayagam A. Treatment of COVID-19-exacerbated asthma: should systemic corticosteroids be used? Am J Physiol Lung Cell Mol Physiol. 2020;318(6):L1244–7.
Wu C, Chen X, Cai Y, Zhou X, Xu S, Huang H, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934–43.
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62.
Group RC. Dexamethasone in hospitalized patients with Covid-19—preliminary report. N Engl J Med. 2020;384:693–704.
Matsuyama S, Kawase M, Nao N, Shirato K, Ujike M, Kamitani W, et al. The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting the viral replication-transcription complex in cultured cells. J Virol. 2020;95(1):e01648-e1720.
Finney LJ, Glanville N, Farne H, Aniscenko J, Fenwick P, Kemp SV, et al. Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon. J Allergy Clin Immunol. 2021;147(2):510-9.e5.
Ramakrishnan S, Nicolau Jr DV, Langford B, Mahdi M, Jeffers H, Mwasuku C, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021;9(7):763–72.
Yu L-M, Bafadhel M, Dorward J, Hayward G, Saville BR, Gbinigie O, et al. Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial. Medrxiv. 2021:2021-04.
Garcia-Vidal C, Sanjuan G, Moreno-García E, Puerta-Alcalde P, Garcia-Pouton N, Chumbita M, et al. Incidence of co-infections and superinfections in hospitalized patients with COVID-19: a retrospective cohort study. Clin Microbiol Infect. 2021;27(1):83–8.
Saade A, Moratelli G, Dumas G, Mabrouki A, Tudesq J-J, Zafrani L, et al. Infectious events in patients with severe COVID-19: results of a cohort of patients with high prevalence of underlying immune defect. Ann Intensive Care. 2021;11(1):1–11.
Søvik S, Barratt-Due A, Kåsine T, Olasveengen T, Strand MW, Tveita AA, et al. Corticosteroids and superinfections in COVID-19 patients on invasive mechanical ventilation. J Infect. 2022;85(1):57–63.
Rosen DA, Seki SM, Fernández-Castañeda A, Beiter RM, Eccles JD, Woodfolk JA, et al. Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med. 2019;11(478):eaau5266.
Rafiee L, Hajhashemi V, Javanmard SH. Fluvoxamine inhibits some inflammatory genes expression in LPS/stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat. Iran J Basic Med Sci. 2016;19(9):977.
Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. JAMA. 2020;324(22):2292–300.
Hoertel N, Sánchez-Rico M, Vernet R, Beeker N, Jannot A-S, Neuraz A, et al. Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study. Mol Psychiatry. 2021;26(9):5199–212.
Takano A, Suhara T, Sudo Y, Inoue M, Hashimoto K, Zhang M-R, et al. Comparative evaluation of two serotonin transporter ligands in the human brain:[11C](+) McN5652 and [11C] cyanoimipramine. Eur J Nucl Med Mol Imaging. 2002;29(10):1289–97.
Hashimoto Y, Suzuki T, Hashimoto K. Mechanisms of action of fluvoxamine for COVID-19: a historical review. Mol Psychiatry. 2022;2022:1–10.
Seftel D, Boulware DR, editors. Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19. Open Forum Infectious Diseases. Oxford University Press US; 2021.
Wen W, Chen C, Tang J, Wang C, Zhou M, Cheng Y, et al. Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: a meta-analysis. Ann Med. 2022;54(1):516–23.
Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet Rheumatology. 2020;2(7):e393–400.
Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, et al. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res. 2020;116(10):1666–87.
La Rosée P, Horne A, Hines M, von Bahr GT, Machowicz R, Berliner N, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465–77.
Mehta P, Porter JC, Manson JJ, Isaacs JD, Openshaw PJ, McInnes IB, et al. Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities. Lancet Respir Med. 2020;8(8):822–30.
Thwaites RS, Uruchurtu ASS, Siggins MK, Liew F, Russell CD, Moore SC, et al. Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19. Sci Immunol. 2021;6(57):eabg9873.
De Luca G, Cavalli G, Campochiaro C, Della-Torre E, Angelillo P, Tomelleri A, et al. GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet Rheumatol. 2020;2(8):e465–73.
Lang FM, Lee KM-C, Teijaro JR, Becher B, Hamilton JA. GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches. Nat Rev Immunol. 2020. https://doi.org/10.1038/s41577-020-0357-7.
Temesgen Z, Assi M, Shweta F, Vergidis P, Rizza SA, Bauer PR, et al. GM-CSF neutralization with lenzilumab in severe COVID-19 pneumonia: a case-cohort study. Mayo Clinic Proc. 2020. https://doi.org/10.1016/j.mayocp.2020.08.038.
Burmester GR, Feist E, Sleeman MA, Wang B, White B, Magrini F. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I, first-in-human study. Ann Rheum Dis. 2011;70(9):1542–9.
Keam S, Megawati D, Patel SK, Tiwari R, Dhama K, Harapan H. Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection. Rev Med Virol. 2020;30(5):e2123.
Galeotti C, Kaveri SV, Bayry J. Intravenous immunoglobulin immunotherapy for coronavirus disease-19 (COVID-19). Clin Transl Immunol. 2020;9(10):e1198.
Shi H, Zhou C, He P, Huang S, Duan Y, Wang X, et al. Successful treatment with plasma exchange followed by intravenous immunoglobulin in a critically ill patient with COVID-19. Int J Antimicrob Agents. 2020;56(2):105974.
Mohtadi N, Ghaysouri A, Shirazi S, Shafiee E, Bastani E, Kokhazadeh T, et al. Recovery of severely ill COVID-19 patients by intravenous immunoglobulin (IVIG) treatment: a case series. Virology. 2020;548:1–5.
Fahmideh H, Shapourian H, Moltafeti R, Tavakol C, Forghaniesfidvajani R, Zalpoor H, et al. The role of natural products as inhibitors of JAK/STAT signaling pathways in glioblastoma treatment. Oxidative Med Cell Longevity. 2022;2022:7838583.
Malekinejad Z, Baghbanzadeh A, Nakhlband A, Baradaran B, Jafai S, Bagheri Y, et al. Recent clinical findings on the role of kinase inhibitors in COVID-19 management. Life Sci. 2022;2022:120809.
Mehta P, Ciurtin C, Scully M, Levi M, Chambers RC. JAK inhibitors in COVID-19: the need for vigilance regarding increased inherent thrombotic risk. Eur Respir J. 2020;56(3):2001919.
Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet (London, England). 2020;395(10223): e30.
Guimarães PO, Quirk D, Furtado RH, Maia LN, Saraiva JF, Antunes MO, et al. Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;385(5):406–15.
Deftereos SG, Siasos G, Giannopoulos G, Vrachatis DA, Angelidis C, Giotaki SG, et al. The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): rationale and study design. Hellenic J Cardiol. 2020;61(1):42–5.
Gao L, Xu J, Chen S. In silico screening of potential Chinese herbal medicine against COVID-19 by targeting SARS-CoV-2 3CLpro and angiotensin converting enzyme II using molecular docking. Chin J Integr Med. 2020;26(7):527–32.
Tregoning JS, Brown E, Cheeseman H, Flight K, Higham S, Lemm N, et al. Vaccines for COVID-19. Clin Exp Immunol. 2020;202(2):162–92.
Le TT, Andreadakis Z, Kumar A, Román RG, Tollefsen S, Saville M, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020;19(5):305–6.
Conforti A, Marra E, Roscilli G, Palombo F, Ciliberto G, Aurisicchio L. Are genetic vaccines the right weapon against COVID-19? Mol Ther. 2020;28(7):1555–6.
O’Callaghan KP, Blatz AM, Offit PA. Developing a SARS-CoV-2 vaccine at warp speed. JAMA. 2020;324(5):437–8.
Kowalski PS, Rudra A, Miao L, Anderson DG. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol Ther. 2019;27(4):710–28.
Porter KR, Raviprakash K. DNA vaccine delivery and improved immunogenicity. Curr Issues Mol Biol. 2017;22(1):129–38.
Sharpe HR, Gilbride C, Allen E, Belij-Rammerstorfer S, Bissett C, Ewer K, et al. The early landscape of coronavirus disease 2019 vaccine development in the UK and rest of the world. Immunology. 2020;160(3):223–32.
Hosseini SA, Zahedipour F, Mirzaei H, Oskuee RK. Potential SARS-CoV-2 vaccines: concept, progress, and challenges. Int Immunopharmacol. 2021;97:107622.
Ura T, Okuda K, Shimada M. Developments in viral vector-based vaccines. Vaccines. 2014;2(3):624–41.
Kaur SP, Gupta V. COVID-19 vaccine: a comprehensive status report. Virus Res. 2020;288:198114.
Jeyanathan M, Afkhami S, Smaill F, Miller MS, Lichty BD, Xing Z. Immunological considerations for COVID-19 vaccine strategies. Nat Rev Immunol. 2020;20(10):615–32.
Forni G, Mantovani A. COVID-19 vaccines: where we stand and challenges ahead. Cell Death Differ. 2021;28(2):626–39.
Ahmed SF, Quadeer AA, McKay MR. Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies. Viruses. 2020;12(3):254.
Yan Y, Pang Y, Lyu Z, Wang R, Wu X, You C, et al. The COVID-19 vaccines: recent development, challenges and prospects. Vaccines. 2021;9(4):349.
Donaldson B, Lateef Z, Walker GF, Young SL, Ward VK. Virus-like particle vaccines: immunology and formulation for clinical translation. Expert Rev Vaccines. 2018;17(9):833–49.
Chen GL, Coates EE, Plummer SH, Carter CA, Berkowitz N, Conan-Cibotti M, et al. Effect of a chikungunya virus-like particle vaccine on safety and tolerability outcomes: a randomized clinical trial. JAMA. 2020;323(14):1369–77.
Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383(27):2603–15.
Mahase E. Covid-19: Moderna applies for US and EU approval as vaccine trial reports 94.1% efficacy. BMJ Br Med J (Online). 2020;371:m4709.
Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020;369(6499):77–81.
Baraniuk C. What do we know about China’s covid-19 vaccines? BMJ. 2021;373:n912.
Knoll MD, Wonodi C. Oxford–AstraZeneca COVID-19 vaccine efficacy. Lancet. 2021;397(10269):72–4.
Logunov DY, Dolzhikova IV, Shcheblyakov DV, Tukhvatulin AI, Zubkova OV, Dzharullaeva AS, et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet. 2021;397(10275):671–81.
Soiza RL, Scicluna C, Thomson EC. Efficacy and safety of COVID-19 vaccines in older people. Age Ageing. 2020;50(2):279–83.
Mahase E. Covid-19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant. British Medical Journal Publishing Group; 2021.
Anderson G, Reiter RJ. Melatonin: roles in influenza, Covid-19, and other viral infections. Rev Med Virol. 2020;30(3):e2109.
Lescure FX, Honda H, Fowler RA, Lazar JS, Shi G, Wung P, Patel N, Hagino O. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021;9(5):522–32.
Cure E, Cure MC. Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis. Diabetes Metab Syndr. 2020;14(4):405–6.
Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor Fedratinib. J Microbiol Immunol Infect. 2020;53(3):368–70.
Cao Y, Wei J, Zou L, Jiang T, Wang G, Chen L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020;146(1):137-46.e3.
Roschewski M, Lionakis MS, Sharman JP, Roswarski J, Goy A, Monticelli MA, et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci Immunol. 2020;5(48):eabd0110.
Treon SP, Castillo JJ, Skarbnik AP, Soumerai JD, Ghobrial IM, Guerrera ML, et al. The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients. Blood. 2020;135(21):1912–5.
Fancher KM, Pappacena JJ. Drug interactions with Bruton’s tyrosine kinase inhibitors: clinical implications and management. Cancer Chemother Pharmacol. 2020;86(4):507–15.
Rodrigues-Diez RR, Tejera-Muñoz A, Marquez-Exposito L, Rayego-Mateos S, Santos Sanchez L, Marchant V, et al. Statins: could an old friend help in the fight against COVID-19? Br J Pharmacol. 2020;177(21):4873–86.
Cour M, Ovize M, Argaud L. Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure? Springer; 2020.
Roozbeh F, Saeedi M, Alizadeh-Navaei R, Hedayatizadeh-Omran A, Merat S, Wentzel H, et al. Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial. J Antimicrob Chemother. 2021;76(3):753–7.
Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study. Life Sci. 2020;253:117592.
Hu K, Wang M, Zhao Y, Zhang Y, Wang T, Zheng Z, et al. A small-scale medication of leflunomide as a treatment of COVID-19 in an open-label blank-controlled clinical trial. Virol Sin. 2020. https://doi.org/10.1007/s12250-020-00258-7.
Blaszczak A, Trinidad JC, Cartron AM. Adalimumab for treatment of hidradenitis suppurativa during the COVID-19 pandemic: safety considerations. J Am Acad Dermatol. 2020;83(1):e31.
Pang J, Xu F, Aondio G, Li Y, Fumagalli A, Lu M, et al. Efficacy and tolerability of bevacizumab in patients with severe Covid-19. Nat Commun. 2021;12(1):1–10.
Scavone C, Brusco S, Bertini M, Sportiello L, Rafaniello C, Zoccoli A, et al. Current pharmacological treatments for COVID-19: what’s next? Br J Pharmacol. 2020;177(21):4813–24.
Laurence J, Mulvey JJ, Seshadri M, Racanelli A, Harp J, Schenck EJ, et al. Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19. Clin Immunol. 2020;219:108555.
Romanelli A, Mascolo S. Sirolimus to treat SARS-CoV-2 infection: an old drug for a new disease. Respir Med. 2020;8(4):420–2.
Bengtson CD, Montgomery RN, Nazir U, Satterwhite L, Kim MD, Bahr NC, et al. An open label trial to assess safety of losartan for treating worsening respiratory illness in COVID-19. Front Med. 2021;8:152.
Acanfora D, Ciccone MM, Scicchitano P, Acanfora C, Casucci G. Sacubitril/valsartan in COVID-19 patients: the need for trials. Eur Heart J Cardiovasc Pharmacother. 2020;6(4):253–4.
Pedrosa MA, Valenzuela R, Garrido-Gil P, Labandeira CM, Navarro G, Franco R, et al. Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19. Clin Sci. 2021;135(3):465–81.
Jorge-Aarón R-M, Rosa-Ester M-P. N-acetylcysteine as a potential treatment for COVID-19. Future Med. 2020;15(11):959–62.
Depfenhart M, de Villiers D, Lemperle G, Meyer M, Di Somma S. Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy? Intern Emerg Med. 2020;15:801–12.
Abobaker A, Alzwi A, Alraied AHA. Overview of the possible role of vitamin C in management of COVID-19. Pharmacol Rep. 2020;2020:1–12.
Ebadi M, Montano-Loza AJ. Perspective: improving vitamin D status in the management of COVID-19. Eur J Clin Nutr. 2020;74(6):856–9.
Zahedipour F, Hosseini SA, Sathyapalan T, Majeed M, Jamialahmadi T, Al-Rasadi K, et al. Potential effects of curcumin in the treatment of COVID-19 infection. Phytother Res. 2020;34(11):2911–20.
Zheng F, Zhou Y, Zhou Z, Ye F, Huang B, Huang Y, et al. SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: a randomized, open-label, parallel-group trial. Int J Infect Dis. 2020;99:84–91.
Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, et al. Efficacy and safety of interferon beta-1a in treatment of severe COVID-19: a randomized clinical trial. medRxiv. 2020:2020-05.
Lou Y, Liu L, Yao H, Hu X, Su J, Xu K, et al. Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial. Eur J Pharm Sci. 2021;157:105631.
Dequin P-F, Heming N, Meziani F, Plantefève G, Voiriot G, Badié J, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298–306.
Bani-Sadr F, Hentzien M, Pascard M, N’Guyen Y, Servettaz A, Andreoletti L, et al. Corticosteroid therapy for patients with COVID-19 pneumonia: a before–after study. Int J Antimicrob Agents. 2020;56(2):106077.
Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, et al. Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int J Infect Dis. 2021;103:62–71.
Xiao M, Tian J, Zhou Y, Xu X, Min X, Lv Y, et al. Efficacy of Huoxiang Zhengqi dropping pills and Lianhua Qingwen granules in treatment of COVID-19: a randomized controlled trial. Pharmacol Res. 2020;161:105126.
Cheng L, Guan W, Duan C, Zhang N, Lei C, Hu Y, et al. Effect of recombinant human granulocyte colony—stimulating factor for patients with coronavirus disease 2019 (COVID-19) and lymphopenia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):71–8.
Ibrahim D, Dulipsingh L, Zapatka L, Eadie R, Crowell R, Williams K, et al. Factors associated with good patient outcomes following convalescent plasma in COVID-19: a prospective phase II clinical trial. Infect Dis Ther. 2020;9(4):913–26.
Sekhavati E, Jafari F, SeyedAlinaghi S, Jamalimoghadamsiahkali S, Sadr S, Tabarestani M, et al. Safety and effectiveness of azithromycin in patients with COVID-19: an open-label randomised trial. Int J Antimicrob Agents. 2020;56(4):106143.
Ulrich RJ, Troxel AB, Carmody E, Eapen J, Bäcker M, DeHovitz JA, et al editors. Treating COVID-19 with hydroxychloroquine (TEACH): a multicenter, double-blind randomized controlled trial in hospitalized patients. Open forum infectious diseases. Oxford University Press US; 2020.
Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;382(25):2411–8.
Furtado RH, Berwanger O, Fonseca HA, Corrêa TD, Ferraz LR, Lapa MG, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020;396(10256):959–67.
Ren Z, Luo H, Yu Z, Song J, Liang L, Wang L, et al. A randomized, open-label, controlled clinical trial of Azvudine tablets in the treatment of mild and common COVID-19, a pilot study. Adv Sci. 2020;7(19):2001435.
Doi Y, Hibino M, Hase R, Yamamoto M, Kasamatsu Y, Hirose M, et al. A prospective, randomized, open-label trial of early versus late favipiravir therapy in hospitalized patients with COVID-19. Antimicrob Agents Chemother. 2020;64(12):e01897-20.
Eslami G, Mousaviasl S, Radmanesh E, Jelvay S, Bitaraf S, Simmons B, et al. The impact of sofosbuvir/daclatasvir or ribavirin in patients with severe COVID-19. J Antimicrob Chemother. 2020;75(11):3366–72.
Zhao J, Yang X, Wang C, Song S, Cao K, Wei T, et al. Yidu-toxicity blocking lung decoction ameliorates inflammation in severe pneumonia of SARS-COV-2 patients with Yidu-toxicity blocking lung syndrome by eliminating IL-6 and TNF-a. Biomed Pharmacother. 2020;129:110436.
Sadeghi A, Ali Asgari A, Norouzi A, Kheiri Z, Anushirvani A, Montazeri M, et al. Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial. J Antimicrob Chemother. 2020;75(11):3379–85.
Rahmani H, Davoudi-Monfared E, Nourian A, Khalili H, Hajizadeh N, Jalalabadi NZ, et al. Interferon β-1b in treatment of severe COVID-19: a randomized clinical trial. Int Immunopharmacol. 2020;88:106903.
Colaneri M, Bogliolo L, Valsecchi P, Sacchi P, Zuccaro V, Brandolino F, et al. Tocilizumab for treatment of severe COVID-19 patients: preliminary results from SMAtteo COvid19 REgistry (SMACORE). Microorganisms. 2020;8(5):695.
Chen W, Yao M, Fang Z, Lv X, Deng M, Wu Z. A study on clinical effect of Arbidol combined with adjuvant therapy on COVID-19. J Med Virol. 2020;92(11):2702–8.
Vahedi E, Ghanei M, Ghazvini A, Azadi H, Izadi M, Panahi Y, et al. The clinical value of two combination regimens in the Management of Patients Suffering from Covid-19 pneumonia: a single centered, retrospective, observational study. DARU J Pharm Sci. 2020;28(2):507–16.
Rahmani H, Davoudi-Monfared E, Nourian A, Nabiee M, Sadeghi S, Khalili H, et al. Comparing outcomes of hospitalized patients with moderate and severe COVID-19 following treatment with hydroxychloroquine plus atazanavir/ritonavir. DARU J Pharm Sci. 2020;28(2):625–34.
Xiong W, Wang G, Du J, Ai W. Efficacy of herbal medicine (Xuanfei Baidu decoction) combined with conventional drug in treating COVID-19: a pilot randomized clinical trial. Integr Med Res. 2020;9(3):100489.
Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307–16.
Edalatifard M, Akhtari M, Salehi M, Naderi Z, Jamshidi A, Mostafaei S, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020;56(6):2002808.
Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M, Abbasian L, et al. A randomized clinical trial of the efficacy and safety of interferon β-1a in treatment of severe COVID-19. Antimicrob Agents Chemother. 2020;64(9):e01061-e1120.
Ansarin K, Tolouian R, Ardalan M, Taghizadieh A, Varshochi M, Teimouri S, et al. Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: a randomized clinical trial. Bioimpacts. 2020;10(4):209.
Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136-e.
Hu K, Wang M, Zhao Y, Zhang Y, Wang T, Zheng Z, et al. A small-scale medication of leflunomide as a treatment of COVID-19 in an open-label blank-controlled clinical trial. Virol Sin. 2020;35(6):725–33.
Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857-e.
Group TRC. Dexamethasone in hospitalized patients with Covid-19—preliminary report. The New England journal of medicine. 2020.
Wang M, Zhao Y, Hu W, Zhao D, Zhang Y, Wang T, et al. Treatment of COVID-19 patients with prolonged post-symptomatic viral shedding with Leflunomide—a single-center, randomized, controlled clinical trial. Clin Infect Dis. 2020;73:e4012–19.
Jeronimo CMP, Farias MEL, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (Metcovid): a randomised, double-blind, phase IIb, placebo-controlled trial. 2020.
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569–78.
Dastan F, Nadji SA, Saffaei A, Marjani M, Moniri A, Jamaati H, et al. Subcutaneous administration of interferon beta-1a for COVID-19: A non-controlled prospective trial. Int Immunopharmacol. 2020;85:106688.
Brown S. Hydroxychloroquine vs. Azithromycin for Hospitalized Patients With Suspected or Confirmed COVID-19-Full Text View-ClinicalTrials. gov [Internet]. 2020 [cited 2020 Apr 3]. https://clinicaltrials.gov/ct2/show/study/NCT04329832.
Gharebaghi N, Nejadrahim R, Mousavi SJ, Sadat-Ebrahimi S-R, Hajizadeh R. The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomized placebo-controlled double-blind clinical trial. BMC Infect Dis. 2020;20(1):1–8.
Nojomi M, Yassin Z, Keyvani H, Makiani MJ, Roham M, Laali A, et al. Effect of Arbidol (Umifenovir) on COVID-19: a randomized controlled trial. BMC Infect Dis. 2020;20(1):1–10.
Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2021;384(9):795–807.
Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):24–31.
Chen C-P, Lin Y-C, Chen T-C, Tseng T-Y, Wong H-L, Kuo C-Y, et al. A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease (COVID-19). PLoS ONE. 2020;15(12):e0242763.
Strohbehn GW, Heiss BL, Rouhani SJ, Trujillo JA, Yu J, Kacew AJ, et al. COVIDOSE: a phase II clinical trial of low-dose tocilizumab in the treatment of noncritical COVID-19 pneumonia. Clin Pharmacol Ther. 2021;109(3):688–96.
Shi N, Guo L, Liu B, Bian Y, Chen R, Chen S, et al. Efficacy and safety of Chinese herbal medicine versus Lopinavir-Ritonavir in adult patients with coronavirus disease 2019: a non-randomized controlled trial. Phytomedicine. 2021;81:153367.
Chaccour C, Casellas A, Blanco-Di Matteo A, Pineda I, Fernandez-Montero A, Ruiz-Castillo P, et al. The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine. 2021;32:100720.
Spinner CD, Gottlieb RL, Criner GJ, López JRA, Cattelan AM, Viladomiu AS, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324(11):1048–57.
Tharaux P-L, Pialoux G, Pavot A, Mariette X, Hermine O, Resche-Rigon M, et al. Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet Respir Med. 2021;9(3):295–304.
Holubovska O, Bojkova D, Elli S, Bechtel M, Boltz D, Muzzio M, et al. Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial. medRxiv. 2021;9(9).
Zhang J, Rao X, Li Y, Zhu Y, Liu F, Guo G, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann Intensive Care. 2021;11(1):1–12.
Saber‐Moghaddam N, Salari S, Hejazi S, Amini M, Taherzadeh Z, Eslami S, et al. Oral nano‐curcumin formulation efficacy in management of mild to moderate hospitalized coronavirus disease‐19 patients: an open label nonrandomized clinical trial. Phytother Res. 2021;35(5):2616–23.
Valizadeh H, Abdolmohammadi-Vahid S, Danshina S, Gencer MZ, Ammari A, Sadeghi A, et al. Nano-curcumin therapy, a promising method in modulating inflammatory cytokines in COVID-19 patients. Int Immunopharmacol. 2020;89:107088.
Abd-Elsalam S, Soliman S, Esmail ES, Khalaf M, Mostafa EF, Medhat MA, et al. Do zinc supplements enhance the clinical efficacy of hydroxychloroquine? A randomized, multicenter trial. Biol Trace Elem Res. 2020;2020:1–5.
Castillo ME, Costa LME, Barrios JMV, Díaz JFA, Miranda JL, Bouillon R, et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study. J Steroid Biochem Mol Biol. 2020;203:105751.
Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939.
Abolghasemi H, Eshghi P, Cheraghali AM, Fooladi AAI, Moghaddam FB, Imanizadeh S, et al. Clinical efficacy of convalescent plasma for treatment of COVID-19 infections: results of a multicenter clinical study. Transfus Apheres Sci. 2020;59(5):102875.
Mareev VY, Orlova YA, Plisyk A, Pavlikova E, Matskeplishvili S, Akopyan Z, et al. Results of open-label non-randomized comparative clinical trial:“Bromhexine and spironolactone for coronavirus infection requiring hospitalization (BISCUIT). Kardiologiia. 2020;60(11):4–15.
Maldonado V, Hernandez-Ramírez C, Oliva-Pérez EA, Sánchez-Martínez CO, Pimentel-González JF, Molina-Sánchez JR, et al. Pentoxifylline decreases serum LDH levels and increases lymphocyte count in COVID-19 patients: results from an external pilot study. Int Immunopharmacol. 2021;90:107209.
Abbas HM, Al-Jumaili AA, Nassir KF, Al-Obaidy MW, Al Jubouri AM, Dakhil BD, et al. Assessment of COVID-19 Treatment containing both Hydroxychloroquine and Azithromycin: a natural clinical trial. Int J Clin Pract. 2021;75(4):e13856.
Zhao H, Zhu Q, Zhang C, Li J, Wei M, Qin Y, et al. Tocilizumab combined with favipiravir in the treatment of COVID-19: a multicenter trial in a small sample size. Biomed Pharmacother. 2021;133:110825.
Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(21):2165–76.
Wang J-B, Wang Z-X, Jing J, Zhao P, Dong J-H, Zhou Y-F, et al. Exploring an integrative therapy for treating COVID-19: a randomized controlled trial. Chin J Integr Med. 2020;26(9):648–55.
Veiga VC, Prats JA, Farias DL, Rosa RG, Dourado LK, Zampieri FG, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;2021:372.
Antinori S, Cossu MV, Ridolfo AL, Rech R, Bonazzetti C, Pagani G, et al. Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: clinical outcome and differences in post-treatment hospitalisation status. Pharmacol Res. 2020;158:104899.
Fu W, Liu Y, Liu L, Hu H, Cheng X, Liu P, et al. An open-label, randomized trial of the combination of IFN-κ plus TFF2 with standard care in the treatment of patients with moderate COVID-19. EClinicalMedicine. 2020;27:100547.
Sakoulas G, Geriak M, Kullar R, Greenwood KL, Habib M, Vyas A, et al. Intravenous immunoglobulin plus methylprednisolone mitigate respiratory morbidity in coronavirus disease 2019. Crit Care Explor. 2020;2(11):e0280.
Ramiro S, Mostard RL, Magro-Checa C, Van Dongen CM, Dormans T, Buijs J, et al. Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study. Ann Rheum Dis. 2020;79(9):1143–51.
Consortium WST. Repurposed antiviral drugs for COVID-19—interim WHO SOLIDARITY trial results. N Engl J Med. 2021;384(6):497–511.
Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7(1):e001455.
Saavedra D, Añé-Kourí AL, Sánchez N, Filgueira LM, Betancourt J, Herrera C, et al. An anti-CD6 monoclonal antibody (itolizumab) reduces circulating IL-6 in severe COVID-19 elderly patients. Immunity Ageing. 2020;17(1):1–8.
This manuscript was supported by Pharmacotherapy Department, Faculty of Pharmacy, Bagyattallah University of Medical Sciences, and Tehran Iran.
This study was funded by Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences (IR. TBZMED. VCR. REC, 1397. 487), Tabriz, Iran, (Grant NO: 62379).
Ethics approval and consent to participate
There is no involvement of humans or animals in this study.
Consent for publication
All other authors declare no conflict of interest.
All other authors declare no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Panahi, Y., Gorabi, A.M., Talaei, S. et al. An overview on the treatments and prevention against COVID-19. Virol J 20, 23 (2023). https://doi.org/10.1186/s12985-023-01973-9
- Antiviral agents
- Biologic agents
- Anti-inflammatory agents
- Herbal agents