key: cord-352256-qxdakdk0
authors: Yousefi, Bahman; Valizadeh, Saeid; Ghaffari, Hadi; Vahedi, Azadeh; Karbalaei, Mohsen; Eslami, Majid
title: A global treatments for coronaviruses including COVID‐19
date: 2020-05-11
journal: J Cell Physiol
DOI: 10.1002/jcp.29785
sha: 
doc_id: 352256
cord_uid: qxdakdk0

In late December 2019 in Wuhan, China, several patients with viral pneumonia were identified as 2019 novel coronavirus (2019‐nCoV). So far, there are no specific treatments for patients with coronavirus disease‐19 (COVID‐19), and the treatments available today are based on previous experience with similar viruses such as severe acute respiratory syndrome‐related coronavirus (SARS‐CoV), Middle East respiratory syndrome coronavirus (MERS‐CoV), and Influenza virus. In this article, we have tried to reach a therapeutic window of drugs available to patients with COVID‐19. Cathepsin L is required for entry of the 2019‐nCoV virus into the cell as target teicoplanin inhibits virus replication. Angiotensin‐converting‐enzyme 2 (ACE2) in soluble form as a recombinant protein can prevent the spread of coronavirus by restricting binding and entry. In patients with COVID‐19, hydroxychloroquine decreases the inflammatory response and cytokine storm, but overdose causes toxicity and mortality. Neuraminidase inhibitors such as oseltamivir, peramivir, and zanamivir are invalid for 2019‐nCoV and are not recommended for treatment but protease inhibitors such as lopinavir/ritonavir (LPV/r) inhibit the progression of MERS‐CoV disease and can be useful for patients of COVID‐19 and, in combination with Arbidol, has a direct antiviral effect on early replication of SARS‐CoV. Ribavirin reduces hemoglobin concentrations in respiratory patients, and remdesivir improves respiratory symptoms. Use of ribavirin in combination with LPV/r in patients with SARS‐CoV reduces acute respiratory distress syndrome and mortality, which has a significant protective effect with the addition of corticosteroids. Favipiravir increases clinical recovery and reduces respiratory problems and has a stronger antiviral effect than LPV/r. currently, appropriate treatment for patients with COVID‐19 is an ACE2 inhibitor and a clinical problem reducing agent such as favipiravir in addition to hydroxychloroquine and corticosteroids.

healthcare workers are advised to be vaccinated every year. But sometimes more dangerous and even deadly forms occur that are likely to lead to epidemics and pandemics (Andrews, 2006) .

In late December 2019 in Wuhan, China, several patients were diagnosed with viral pneumonia, now known as the 2019 novel coronavirus (2019-nCoV). Subsequently, a large number of cases of the disease were found to either reside in Wuhan or travel to the city. The researchers were able to obtain the 2019-nCoV genome sequence by performing bronchoalveolar lavage and culture of patients' lungs and by conducting phylogenetic analyzes of the genome and investigating the evolutionary relationship between 2019-nCoV and other coronaviruses, they found the origin of 2019-nCoV and its evolutionary history. The 2019-nCoV genomic sequence obtained from the patients showed that 98.99% of their gene sequences matched. The genome also has an 88% similarity to the genome of the bat-SL-CoVZC45 and bat-SL-CoVZXC21 bat coronavirus genomes that appeared in Zhoushan, China, but with the severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) coronaviruses, 79% and 50% were similar, respectively. Also by homology modeling, a model for the virus receptor was obtained, which, by comparing homology models, concluded that despite differences in some amino acids, the structure of the domains attached to the receptor at 2019-nCoV and SARS-CoV was similar. SARS-CoV spike (S) protein is essential for entry into the host cell. The Spike S1 subunit contains the receptor-binding domain (RBD). The SARS-CoV virus uses the angiotensin-converting-enzyme 2 (ACE2) receptor to bind the host cell, that contains a diversity of respiratory epithelial cells, alveolar macrophages, and monocytes. Considering the relatively high identity of the RBD in 2019-nCoV and SARS-CoV, it is crucial to evaluate the cross-reactivity of anti-SARS-CoV antibodies with 2019-nCoV spike protein, which could have significant implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. These structures displayed that SARS-CoV RBD contains a core structure and a receptor-binding motif (RBM), and that the RBM binds to the outer surface of ACE2. The ACE2 is the only known human homolog of the key regulator of blood pressure ACE.

SARS-CoV-2 RBD showed significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the connection and, therefore, binding of SARS-CoV-2 and SARS-CoV RBD to ACE2expressing cells, so inhibiting their infection to host cells. Therefore, ACE2 also serves as the cellular entry site for the SARS-CoV, a main target for pharmacological intervention and improved new monoclonal antibodies that could attach specifically to 2019-nCoV RBD.

SARS-CoV RBD-specific antibodies possibly will cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could neutralize SARS-CoV-2, suggesting the potential to improve SARS-CoV RBD-based vaccines for inhibition of SARS-CoV-2 and SARS-CoV infection (Tai et al., 2020; Wan, Shang, Graham, Baric, & Li, 2020) .

Bats host a reservoir of various zoonotic viruses, including coronaviruses. Regulatory studies and phylogenetic analyzes have shown that there is a high genetic diversity among SARS-like viruses in bats, allowing for the recombination and evolution of new species.

It has been shown that the bat virus with 96% nucleotide sequence similarity to human SARS-CoV can use human ACE2 as a receptor. This represents the same state of entry into the cell as human SARS-CoV. For example, bat SL-CoV-WIV1 can grow on human epithelial cells and Vero E6 cells, which is neutralized by human SARS-CoV convalescent sera (Ge et al., 2013; Yang et al., 2016) . The recent crisis was the outbreak of novel Coronavirus from emerged Wuhan in central China, referred to as 2019-nCoV, has recently caused a pandemic scale of pneumonia in humans and resulted in a huge threat to the global public and a high number of hospitalizations. The damage to the lungs, which leads to fluid leaking from small blood vessels in the lungs. The fluid collects in the lungs' air sacs or alveoli. This makes it difficult for the lungs to transfer oxygen from the air to the blood. While there's a shortage of information on the type of damage that occurs in the lungs during 2019-nCoV Wu, Leung, & Leung, 2020 A glycopeptide antibiotic commonly used to treat a bacterial infection is active against SARS-CoV and is on the list of drugs that are also used to treat COVID-19 (J. . This antibiotic is Chloroquine has recently been shown to be an inhibitor of SARS-CoV-2 in vitro and the hydroxylated form has been suggested as a potential treatment for patients with SARS-CoV-2 infection. Importantly, the overdose of this drug is toxic and can cause death (Devaux, Rolain, Colson, & Raoult, 2020; Weniger & World Health Organization, 1979) . M. Wang et al. (2020) reported that the EC50 of Chloroquine against COVID-19 tested on VERO E6 was 1.13 μM and the EC90 was 6.90 μM. Chloroquine inhibits SARS-CoV entry, which exerts its inhibitory effect by altering glycosylation of the ACE2 receptor and spike protein. In patients with COVID-19, hydroxychloroquine has been shown to decrease inflammatory responses and decrease cytokine storm in vitro. Chloroquine also interferes with proteolytic processing of M protein and modifies virion assembly and budding. Also, chloroquine indirectly act against COVID-19 by reducing the production of proinflammatory cytokines and by activating anti-SARS-CoV-2 CD8 + T-cells (Devaux et al., 2020) . It has also been used in the treatment of intracellular bacterium Coxiella burnetii both in vitro and in vivo and has resulted F I G U R E 1 Molecular mechanisms and therapeutic targets of drugs that have been used to treat COVID-19. ACE2, angiotensin-converting enzyme 2 receptor; COVID-19, coronavirus disease-19; ER, endoplasmic reticulum; IMPDH, inosine monophosphate dehydrogenase; RdRp, RNA-dependent RNA polymerase in its elimination (Savarino, 

Lopinavir is an antiretroviral protease inhibitor used in combination with ritonavir to treat patients with AIDS and HIV infection.

Lopinavir is a potent and highly specific inhibitor of HIV-1 protease.

Ritonavir inhibits the metabolism of lopinavir, therefore coadministration of lopinavir and ritonavir in healthy volunteers increases the area under the lopinavir plasma concentration-time curve> 100-fold (Hurst & Faulds, 2000) . In a study by Cao et al. (2020) , can be obtained (Lim et al., 2020) . But in a study by Jun Zhang at Xixi hospital in Hangzhou, China. A 2020 study showed that 400 mg daily lopinavir with IFN-α2b atomization inhalation, 5 million U twice daily, as well as the use of lopinavir alone could be useful for patients with COVID-19 and increased eosinophils have been suggested as an indicator of improvement in patients, But after starting treatment with this drug, complications such as digestive adverse effect and hypokalemia should be considered by physicians .

Jinyu Xia's study also showed that the combined effect of Arbidol with LPV/r was greater than that of LPV/r (16 patients received oral Arbidol with LPV/r and 17 patients received LPV/r alone).

Arbidol has been shown to have a direct antiviral effect on the initial in vitro replication of SARS-CoV (Deng et al., 2020; Khamitov et al., 2008) . Arbidol (Umifenovir) is a broad-spectrum antivirus that works on both enveloped and nonenveloped viruses. It is active on viruses such as influenza A and B and is also known to inhibit hepatitis C. This drug can prevent the fusion of the virus with the target membrane and block the entry of the virus into the target cell (Boriskin, Leneva, Pecheur, & Polyak, 2008 ).

Oseltamivir is a neuraminidase inhibitor (NAIs) used to treat influ- Of recent concern about the use of oseltamivir was the emergence of resistance in 23% of patients with H1N1, which was asso- 

Ribavirin is a guanosine nucleoside analog and antiviral compound (Graci & Cameron, 2006; Martinez, 2020) . In animal studies of coronaviruses, ribavirin, although weakly inhibitory, can reduce the release of macrophage proinflammatory cytokines in mice and alter the Th-2 response to Th-1 response and act as an immunomodulator (Ning et al., 1998) . In most cases, ribavirin is combined with IFN, and although the results of ribavirin and IFNα-2b YOUSEFI ET AL.

| 5 in a MERS-CoV rhesus macaque model were promising, with the results of the trial and the effect of ribavirin and IFN (either α2a or β1) on MERS-CoV infected patients it was different, however, ribavirin lowers hemoglobin concentrations in respiratory patients and therefore reduces its potential as an antiviral against SARS-CoV-2 (Arabi et al., 2017; Falzarano et al., 2013) . IFNα-2b and ribavirin, when used for MERS-CoV treatment, showed that they were 8-fold and 16-fold reduced in their single-dose regimen, respectively and they further stimulate cytokine release and immune responses, reducing viral replication, modulating host response, and improving clinical outcomes. Studies using ribavirin plus lopinavir/ritonavir on patients with SARS have reduced ARDS and mortality. There was also a significant decrease in ARDS and mortality in patients with SARS-CoV who received corticosteroids with ribavirin, lopinavir/ ritonavir (Chu et al., 2004; Zheng & Wang, 2016 ).

Favipiravir (FPV) a guanosine analog and an oral anti-influenza drug that targets RNA-dependent RNA polymerase (RdRP), which converts to active phosphoribosylated form in cells and acts as an RNA polymerase inhibitor. Also, favipiravir is a broad-spectrum drug that blocks the replication of flavivirus, poliovirus, rhinovirus, filovirus, and arenaviruses. The effective dose of favipiravir used is Day 1:

1,600 mg twice daily, Days 2-5: 600 mg twice daily but its effective dose for treatment of COVID-19, and 600 mg tid with 1,600 mg first loading dosage for no more than 14 days. However, favipiravir is contraindicated in pregnant women due to teratogenicity and embryotoxicity in animals and cannot be used in this group of patients (Delang, Abdelnabi, & Neyts, 2018; Shiraki & Daikoku, 2020) .

A study by Fang et al. (2020) found that favipiravir could play an important role in protecting mice from the fatal infection of wild-type and oseltamivir-resistant-influenza B viruses. Favipiravir has also been used in combination with zanamivir to successfully clear the type B influenza virus in immunocompromised children (Lumby et al., 2020) . In a randomized clinical trial, Chen et al. (2020) showed that in patients with moderate COVID-19 who were untreated with antiviral drugs, favipiravir increased clinical recovery over 7 days and reduced fever, cough, and respiratory problems, it was therefore used as an effective drug in these patients. Another study by Jianjun

Gao on 80 patients with COVID-19 at the Hospital of Shenzhen, China, showed that favipiravir had a stronger antiviral effect than the lopinavir/ritonavir drug combination and reported no adverse effects (Furuta, Komeno, & Nakamura, 2017) . 

A cellular inosine monophosphate dehydrogenase inhibitor and an immunomodulator that has antiviral effects on a range of viruses, including influenza A, reovirus, flavivirus, and coxsackie B3 virus, it is also used as an inhibitor of nucleotide synthesis in lymphocytes and an immunosuppressant in transplantation and treatment of autoimmune diseases (Diamond, Zachariah, & Harris, 2002; Padalko et al., 2003) . It has also been shown to inhibit hepatitis B and hepatitis C virus replication in combination with IFN-α and cyclosporine A. Mycophenolic acid (MPA) in use with cyclosporine, it is also a potent inhibitor of MERS-CoV but has a less inhibitory effect on SARS-CoV. In studies of coronaviruses in the mouse model, it did not affect SARS-CoV, but at standard concentrations at oral doses, it was able to inhibit MERS-CoV (Chan et al., 2013; Henry et al., 2006; Markland, McQuaid, Jain, & Kwong, 2000) .

MPA acts as a synergism with IFN-β1b and thiopurine analogs but it has less protective effect than the combined effect of 6 | lopinavir/ritonavir with IFN-β1b. The use of this compound in bedside coronaviruses was that with the IFN-β1b used in Saudi Arabia to treat MERS-CoV all patients using this drug combination could survive but patients had lower acute physiology and chronic health (Allison & Eugui, 1993) . MPA also had a significant inhibitory effect on the proliferation of HCoV-OC43 and HCoV-NL63 at EC50

concentrations of 1.95 μM and 0.19 μM, respectively (Shen et al., 2019) . Lin et al. (2018) also showed that MPA along with disulfiram and 6-thioguanine was synergistically inhibitors of the MERS-CoV papain-like protease (MERS-CoV PL pro ).

Angiotensin-converting enzyme 2 gene (ACE2) is a metalloproteinase with 805 amino acids which is an important receptor for entry of SARS-CoV into the host cell. Domain S1 in the SARS-CoV spike protein binds the virus to the ACE2 cell receptor present in the host cells. Therefore understanding the association between SARS-CoV, SARS-CoV-2, and ACE2 can be an effective therapeutic approach (Lin et al., 2018) . ACE2 is a homolog of carboxy peptidase that is best known for cleaving different peptides in the renin-angiotensin system (RAS) and other substrates, such as apelin (Batlle, Wysocki, & Satchell, 2020) . This enzyme is mostly present in organs such as the kidneys, gastrointestinal tract, and relatively low level in the lungs and its expression has been reported in Type 2 pneumocytes (Hamming et al., 2004) . The extracellular domain of ACE2 acts as the SARS-CoV and SARS-CoV-2 spike protein receptor. The new coronavirus also uses membrane-bound ACE2 as the receptor. ACE2

neutralizes SARS-CoV-2 in vitro by combining with the Fc protein of immunoglobulin (Lei et al., 2020) . In addition, SARS-CoV-2 binds to ACE2 with a higher affinity than SARS-CoV. In this context, the preparation of a soluble and recombinant form of ACE2 protein in humans could be useful as a novel biological treatment to counter or limit the progression of infection caused by coronaviruses that use ACE2 as a receptor (Wrapp et al., 2020 to treat COVID-19, it is clear that the use of these drugs alone will not produce the desired results, and some drugs will cause side effects in certain groups of people. For example, excessive use of chloroquine is toxic and can even be fatal, or the use of favipiravir in pregnant women is not recommended, as it is associated with teratogenicity and embryotoxicity in animals or corticosteroids that are immunosuppressive and are not recommended for mild or early ARDS, because early use of corticosteroids can delay the clearance of the virus and increase the risk of death, long-term administration of high doses of corticosteroids in the early stages of treatment has negative effects. Generally, corticosteroids should be avoided unless the patient has symptoms such as moderate or severe ARDS, sepsis or septic shock. MPA also has no effective inhibitory effect on SARS-CoV, so they are not recommended for treatment. Lopinavir is associated with side effects such as digestive adverse effects and hypokalemia that should be considered by physicians. The use of neuraminidase inhibitors is also invalid due to resistance to nCoV-2019 and is not recommended for the treatment of patients.

However, the use of hydroxychloroquine as prophylaxis is appropriate because it blocks the entry of the virus and prevents virus replication, and remdesivir has extensive antiviral activity against coronaviruses. Therefore, the appropriate recommendation for the treatment of patients with COVID-19 is a combination of existing drugs. IFNα-2b together with ribavirin, when used for the treatment of MERS-CoV, showed that their effective dose was decreased compared to the single-dose regimen and better-stimulated cytokine release and inflammatory responses, and decreased viral replication, modulated host response, and improved clinical outcomes.

Ribavirin plus lopinavir/ritonavir in patients with SARS-CoV reduces ARDS and mortality, and in patients with SARS-CoV who receive corticosteroids with ribavirin, lopinavir/ritonavir, their ARDS and mortality significantly decreased. Lopinavir also has a stronger antiviral effect than the LPV/r, and the combination of arbidol and LPV/r is more effective than LPV/r. In addition to these drugs, if ACE2 is presented in its soluble form as a suitable recombinant protein, it may be a new factor in counteracting the spread of coronavirus as well as its proliferation in infected individuals. Another possible treatment option could be the use of serums that are obtained from the blood of patients infected with the new coronavirus during their recovery and also targeting the cellular components involved in the host's inflammatory response to the virus is also a good way of targeting viral damage by targeting a cellular protein.

YOUSEFI ET AL.

Effectiveness of antiviral treatment in human influenza A (H5N1) infections: Analysis of a global patient registry

Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil

The flu…and you

Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome

Effect of ribavirin and interferon on the outcome of critically Ill patients with MERS. Viral Respiratory Infections

Soluble angiotensinconverting enzyme 2: A potential approach for coronavirus infection therapy

Oseltamivir resistance in severe influenza A (H1N1) pdm09 pneumonia and acute respiratory distress syndrome: A French multicenter observational cohort study

Arbidol: A broadspectrum antiviral compound that blocks viral fusion

Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus

Favipiravir versus arbidol for COVID-19: A randomized clinical trial. medRxiv

Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings

Favipiravir as a potential countermeasure against neglected and emerging RNA viruses

Arbidol combined with LPV/r versus LPV/r alone against corona virus disease 2019: A retrospective cohort study

New insights on the antiviral effects of chloroquine against coronavirus: What to expect for COVID-19?

Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA

Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques

Effectiveness of favipiravir (T-705) against wildtype and oseltamivir-resistant influenza B virus in mice

Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase

Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor

Mechanisms of action of ribavirin against distinct viruses

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-α

What can we predict about viral evolution and emergence? Current Opinion in

LB16. Phase 3 trial of Baloxavir Marboxil in high-risk influenza patients (CAPSTONE-2 study)

Efficacy and safety of glucocorticoids in the treatment of severe communityacquired pneumonia: A meta-analysis

Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures

Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China

Potent neutralization of 2019 novel coronavirus by recombinant ACE2-Ig

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

Case of the index patient who caused tertiary transmission of Coronavirus disease 2019 in Korea: The application of lopinavir/ ritonavir for the treatment of COVID-19 pneumonia monitored by quantitative RT-PCR

Disulfiram can inhibit mers and sars coronavirus papain-like proteases via different modes

Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression

GS-5734 and its parent nucleoside analog inhibit filo-, pneumo-, and paramyxoviruses

Developing therapeutics for Ebola virus disease: A multifaceted approach, Neglected tropical diseases: Drug discovery and development

Favipiravir and zanamivir cleared infection with influenza B in a severely immunocompromised child

Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: A comparison with ribavirin and demonstration of antiviral additivity with alpha interferon

Compounds with therapeutic potential against novel respiratory 2019 coronavirus

A randomized, controlled trial of Ebola virus disease therapeutics

Ribavirin inhibits viral-induced macrophage production of TNF, IL-1, the procoagulant fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response

Mycophenolate mofetil inhibits the development of Coxsackie B3-virus-induced myocarditis in mice

Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis

Surviving sepsis campaign: International guidelines for management of sepsis and septic shock

New insights into the antiviral effects of chloroquine

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

High-throughput screening and identification of potent broadspectrum inhibitors of coronaviruses

Favipiravir, an anti-influenza drug against life-threatening RNA virus infections

Human coronavirus-receptor interactions

Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine

An evaluation of chloroquine as a broad-acting antiviral against hand, foot and mouth disease

Pulmonary pathology of early phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer

Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza

Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus

Prompt oseltamivir therapy reduces medical care and mortality for patients with influenza infection: An asian population cohort study

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Review of side effects and toxicity of chloroquine

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. roceedings of the National Academy of Sciences of the United States of America

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: A modelling study

Antimalaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model

Isolation and characterization of a novel bat coronavirus closely related to the direct progenitor of severe acute respiratory syndrome coronavirus

Influenza-like illness caused by the 2019 novel coronavirus (2019-nCoV) via the person-to-person transmission. Preprints

Teicoplanin potently blocks the cell entry of 2019-nCoV

Bioinformatics analysis on molecular mechanism of ribavirin and interferon-α in treating MERS-CoV

Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia

A global treatments for coronaviruses including COVID-19