SARS-CoV-2, the novel coronavirus strain responsible for the current pandemic of COVID-19, has rendered the entire humanity suffering. Several months have passed since the pandemic has struck. However, the world is still looking for an effective treatment plan to battle the viral infection. The first vaccine just received emergency approval in December 2020 for use in USA and UK. These are excellent news, however, the worldwide distribution of such vaccine, the possibility of virus mutation and the lack of data regarding the long-term effects of such vaccines are a significant concern. In addition, although remdesivir was recently approved by the FDA to be used as a clinical drug against COVID-19, it hasn’t stood out yet as a proven form of therapeutics. Such inability to produce a novel therapy has caused enough inconveniences for the affected people worldwide. Repurposing the already available drugs to fight against the virus seems to be a reasonable option amidst such uncertainty. Given the vast collection of potential treatment candidates to be explored against COVID-19, there is a decent chance that a success in this regard will serve the intermediary purpose of clinically treating the infection until a COVID-19 vaccine is widely distributed worldwide and will be able to treat COVID-19 patients that do not adequately respond to vaccines. Such treatments may prove very useful in future coronavirus outbreaks too. Proper research into these repurposing treatments may yield a certain insight into the field of novel treatment production as well. This review study accumulates a relevant set of information about drugs and vaccines against COVID-19, in terms of their repurposing properties and the specific phases of clinical trials they are undergoing across the world.  A potential timeline is also suggested to estimate when an effective result can be expected from the ongoing clinical trials for a better anticipation of the drug landscape. This study will hopefully help accelerate investment of resources into development and discovery of drugs and vaccines against the infection. Introduction12. History of COVID-19 and its Treatment3. Methodology and Sources4. COVID-19 Drug R&D Landscape5. Types of Treatments in Clinical Trial5.1 Biological Treatments5.2 Chemically Derived Drugs6. Vaccines7. Countries and Sponsors Involved in Drug Trials8. Timeline and Clinical Trial Phases9. Conclusion1,2. This inability to produce a cure is surprisingly consistent with no approved medication being present for previous two major coronavirus outbreaks (SARS-CoV in 2003 and MERS-CoV in 2015) from the same genus3,4. An effective vaccine is important in order to obtain herd immunity5. The first vaccine just received emergency approval in December 2020 for use in USA and UK. However, it will take months to have it distributed worldwide, its long-term effects are hard to predict, and the possibility of future resistant mutations is a concern. In addition, because of novelty of the SARS-CoV-2 strain and its constant mutative nature, it is hard to synthesize a universal vaccine, so soon enough to be used across the globe right now6,7. In fact, SARS-CoV-2 has affected almost all the countries and provinces in the world and needs immediate attention by extensive approaches to sidestep the symptoms and the disease in a steady manner8,9. Having that in focus, repurposed drugs may serve as an intermediate purpose of treating the disease until a stronger novel drug or an universal vaccine is developed. Repurposed drugs simply work following a manipulated mechanism in already approved drugs for other conditions directed towards weakening the SARS-CoV-2 in a system10. Research into such an area requires a landscape of probable drug candidates to be observed on a regular basis. Now, a good number of drug companies, industries and other institutions around the world are investing into developing aptly repurposed drugs to tackle this global crisis. Here, we have compiled information about 876 clinical trials of various drugs that are currently being researched through tests to be finalized as drug candidates. We have categorized the drugs in terms of their nature to serve a better understanding of the purposes of each drug and the duration the drugs may require completing the clinical trial. By a comparative arrangement, we have presented a dynamic view of drugs to figure out their true potentials.SARS-CoV-2, a new coronavirus strain detected in Wuhan City, Hubei Province, China is the infectious agent behind the coronavirus disease, 2019 (COVID-19), for which no efficient treatment is available to date11,12. Being zoonotic in nature, it is believed that coronaviruses spread to humans from animals. Two cases were previously reported where human infections resulted in drastic disease. The first one was the 2002-2004 SARS outbreak, when humans got infected via the betacoronavirus named SARS-CoV, which is usually found in bats, resulting in 8,422 infections and 916 deaths around the world13. The second one was also produced by a betacoronavirus named MERS-CoV, initiated in Saudi Arabia in 2012, affecting about 3,000 people with concomitant 858 deaths14. The outbreak was well controlled at that time, although the virus came back a couple of times, causing separate outbreaks in South Korea (2015) and in Saudi Arabia (2018)15. MERS and SARS outbreaks never turned into pandemics because of two principal reasons. The first reason is that the reproductive value or R of both SARS-CoV and MERS-CoV were too low (2 or 3 for SARS CoV and below 1 for MERS-CoV), which means that from one infected person two or three more could be infected further. Hence, they were less contagious and avoiding close contact alone could suppress the possibility of being exposed to the diseases16,17. Unfortunately, in the case of SARS CoV-2, the R is around 4, which makes it more intimidating than any other viruses, despite having weaker manifestations18. The second reason is that the affinity of SARS-CoV-2 for angiotensin-converting enzyme 2 (ACE2) receptor is higher than that of SARS-CoV.SARS‑CoV‑2 belongs to the subfamily Orthocoronavirinae, family Coronaviridae, order Nidovirales. It comprises of four subtypes with two among them, named α and β, infecting humans, whereas the other two, named γ and δ, more likely to infect animals. It is only the seventh coronavirus known to infect humans until now and only the third to have caused a severe outbreak after SARS-CoV and MERS-CoV. Other coronaviruses, such as HKUI, NL63, OC43 and 229E manifest with milder symptoms compared to the ones in Betacoronavirus genus19. Implementation of systemic corticosteroids following the example of SARS‑CoV to treat pneumonia associated with COVID-19 showed, at least initially, no benefits either12. World Health Organization (WHO) constituted an R&D blueprint to draw suitable therapeutic methods to respond to the virus that included design and development of drugs, vaccines and other clinical techniques. Accompanied by European Medicines Agency, US Food and Drug Administration (FDA) and the Chinese government itself, WHO has already initiated materializing their goals by assembling resources and researchers to delve into establishing efficient vaccines and drugs.As far as drug R&D is concerned, several desperate attempts have been made to treat the COVID-19 since the onset of the emergence of the virus in China. Apparently, the very first approach was made through traditional Chinese medicine therapies (TCM) back in China in December 2019. Although none of those medications were designed exclusively for COVID-19, YinHuQingWen decoction and ShuFengJieDu capsules were suggested in preliminary case treatment with no effective resultwww.clinicaltrial.gov in 4 different categories: “Not yet recruiting”, “Recruiting”, “Enrolling by invitation” and “Active, not recruiting”. We considered going through drugs in all the study phases available including the non-applicable ones with no designation. Since we were studying clinical trials for the landscape, we emphasized on interventional study type of drugs. In addition to this systematic algorithm, we sought assistance from regular and contemporary literature reviews on drugs and vaccines landscape, in order to stay updated with our approach.We retrieved information from the register of Figure 1).To date, resources are being invested more in the reinforcement of repurposing drugs suiting to COVID-19 cases than in developing novel drugs. That is because of: firstly, synthesizing a novel drug to combat the pandemic at the present time is highly unlikely to serve any purpose considering the unavailability of one perfect design or strategy and also requirement of a huge amount of time. Rather, to make the best use of existing drugs by manipulating them to fight against COVID-19 seems a much smarter approach, if it works. Secondly, in some cases of repurposing drugs, some clinical phases may not be required (phases I and II). Therefore, the drugs may become available on the market faster as compared to the novel ones. Thirdly, both pharmaceutical supply chains and distribution are readily available for such drugs. Besides, applying such drugs in combination with another drug may prove to be much more effective than monotherapy. And the last but not the least, drug repurposing may lead to discovery of new mechanisms of action for old drugs and may pave a way for a new target-based therapeutic in the process as well .In current clinical drug research, as of 5Figure 3A), antibody-mediated ones are mostly prevailing, especially tocilizumab and sarilumab being widely used in clinical trials. Convalescent plasma-based treatments are also being evaluated in clinical trials in large facilities, where plasma from cured patients is transferred to the infected patients. Another potential biological target for drug development is the use of stem cell. Several types of mesenchymal stem cells are now being tested as a treatment for COVID-19 patients. Other prospective biological drugs in clinical trials include interferons and NK cells. Even enzymes and peptide-based drugs are under consideration for decisive clinical trials (Table 2).Among the biological treatments  reported improved respiratory status, viral loads and pulmonary lesions in patients administered with convalescent plasma leading to a meaningful recovery. However, no conclusive remarks on the efficacy of the therapy were made by the author. The result of another single ongoing clinical trial to determine the efficacy of anti-SARS-CoV-2 inactivated convalescent plasma remains to be seen30. Many clinical trials are currently being registered to observe effects of convalescent plasma in COVID-19 recovery .Convalescent plasma treatment involves transfusion of plasma content enriched with antibodies from a system exposed to a particular pathogen31. Combined with other drugs or even alone, interferon can demonstrate a diverse antiviral quality against multiple viruses, such as HCV, respiratory syncytial virus32, and α2β has already been declared to have inhibitory effects on both MERS-CoV and SARS-CoV33. Thus, numerous clinical trials are focusing on the safety and feasibility of the interferon treatment program for COVID-19 management (NCT04293887). Few other clinical trials on peginterferon products are under consideration in United States  and in Canada (NCT04354259).Virus infected cells naturally secrete type-1 interferon31. Preclinical trials demonstrated that MSCs coupled with the ability of decreasing inflammatory infiltrate serve to retain endothelial permeability34. Immunomodulating effects of mesenchymal stem cells have already been proven to be effective on avian influenza viruses35. Presently, MSCs extracted from dental pulp and umbilical cord are being experimented for clinical use against COVID-19 31. A study by University of Utah on MSCs out of amniotic fluid is in the earliest stage now (NCT04319731).Stem cell research has been on the table for quite a long time now and mesenchymal stem cell (MSC) is being evaluated extensively for COVID-19. MSCs are basically anti-inflammatory agents that produce paracrine factors to repair damaged tissues and reduce pro-inflammatory cytokines at the same time36. Thus, it is obvious that producing SARS CoV-2 surface specific and epitope-targeting antibodies should be the sustainable and long term solution for COVID-1937. AbCellera from Canada and Eli Lilly and Company from USA are collaborating to develop a functional antibody for neutralizing SARS-CoV-2 from around 500 potential antibody sequences, by screening over 5 million immune cells from one of the early COVID-19 patients in USA31. A significant number of clinical trials focused on antibodies is being conducted, with more emphasis than on other biological drugs . Intravenous immunoglobulin (IVIG) also exploits a dynamic range of effects on the immune system depending upon doses applied31. As for the low doses of 0.2-0.4g/kg, IVIG works as a replacement therapy in antibody deficiency cases, whereas for higher doses of 2g/kg, IVIG displays its immunomodulating features by inhibiting inflammatory cells proliferation, antibody-dependent cytotoxicity and suppressing phagocytosis38. However, contemporary clinical trials against COVID-19 are focusing only on the low doses of IVIG (NCT04261426)31. Several clinical trials were performed to determine the effectiveness of human immunoglobulin in patients with pneumonia caused by 2019-nCoV33,including one by the Versailles Hospital (NCT04403269) in France and in Spain (NCT04432324).Pathogen specific antibodies as a part of humoral immune response have always been considered a formidable solution against viral infections. Screening cells and manufacturing specific antibodies for this purpose are rather time-consuming and require incessant labor, yet have been massively successful against the West Nile Virus39. Natural killer (NK) cells are important parts of innate immunity system to elicit immediate response against viral infections31. The NK group 2 member A (NKG2A) receptors basically reduce mechanism of action of NK cells to a minimal level40. Overexpression of NKG2A compromises basic innate responses by exhausting both NK cells and CD8+ cells, whereas several other studies on cancers revealed that blocking NKG2A on those cells restores CD8+ and NK cells functions41 and significantly inhibits tumor growth42. Studies have shown that pulmonary migration of NK cells and macrophages exert a special role in eliminating SARS-CoV43. This innate response promotes a stable immunity against the SARS-CoV regardless of assistance from antibodies or CD8+ cells by producing cytokines and chemokines31. A similar approach is in clinical trials in China to unravel whether the same outcome is reproducible in the case of COVID-19 (NCT04280224)29. Many companies attempted to treat COVID-19 via repurposed NK-based products. The Kleo Pharmaceuticals from USA, in association with a South Korean Green Cross LabCell company are working together to develop such products. The placental haematopoetic stem cell-derived NK cells, CYNK-001 is developed by a company named Celularity from USA (NCT04365101)39.Until today, the highest mortality caused by COVID-19 is seen among elder patients, which to some extent, may be related to the decreasing immune system with age. Therefore, efforts should be made to speed up the innate anti-viral immune responseFigure 3B). The most talked about among them is hydroxychloroquine, an antimalarial drug reported to have more credibility in eliminating the symptoms than any other, although no peer review article has ever confirmed it44 as of the time we are writing this review. Even a combination of hydroxychloroquine and some other drugs like azithromycin is being tested on subjects to find out whether the supposed inclination towards this particular drug is to be attended to or not. About 542 chemical drugs are under incessant clinical trials around the world and about 150 of them pertaining to hydrochloroquine, chloroquine and their combinations are under rapid clinical trials, making this a statistically significant investment behind one particular type of drug (Table 3). Lopinavir and ritonavir, drug combination used against HIV is also listed as one of the most researched ones. Several antiviral drugs are presented too, with remdesivir, favipiravir being the notable ones. Some of the other chemical drugs which got the most focus are azithromycin, losartan, colchicine, enoxaparin, ivermectin and nitric oxide. Traditional Chinese medicine therapy has also been an initial approach to fight back in China during the onset of the outbreak and is still being researched to this day45.Chemically derived drugs are comparatively more diverse, as can be determined from this evaluation  and in different combinations . A randomized, double-blind, placebo-controlled, multicenter clinical trial at ten hospitals in Hubei, China revealed that remdesivir use was not associated with a difference in time to clinical improvement in patients compared to subjects receiving placebo. The US National Institutes of Health (NIH) conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement. Study revealed that those who received remdesivir had a median recovery time of 11 days as compared with 15 days in those who received placebo. The Food and Drug Administration (FDA) had made remdesivir available under an emergency-use authorization for the treatment of adults and children with severe COVID-19 disease in early May. In late May, FDA officially issued a conditional approval for remdesivir in Taiwan and eventually other countries like EU and Canada started to adopt the legal approval for a regular use against the disease52.Remdesivir has been one of the most controversial entries for clinical drug trials against COVID-19. The drug has shown enough credibility and all-encompassing properties against RNA viruses particularly53. Favipiravir follows the mechanism of competitive inhibition to alter the activity of RNA-dependent RNA-polymerase, by resembling the structural makeup of endogenous guanine54. The drug is already approved for influenza and has also been designated by National Medical Products Administration in China as the first anti-COVID-19 drug of the country31. Repurposing favipiravir for COVID-19 is much of a challenge because of lesser preclinical trials on the drug compared to remdesivir, although both of them are similar in terms of their actions31. Number of favipiravir clinical trials  is marching on with increasing expectations. Stanford Medicine researchers launched a clinical trial to test whether an oral drug can reduce symptoms and viral shedding in people with COVID-19 beginning in July 655. Simultaneously, Glenmark is conducting phase III clinical trials of favipiravir as a COVID-19 monotherapy option with 150 patients, enrolled from 9 leading government and private hospitals across India.The drug favipiravir branded as Avigan was developed by Toyama Chemical 31. Ritonavir combined with lopinavir leads to increased plasma half-life. Such combination was reported to lead to decreased adverse results in the 2004 SARS outbreak30. Studies showed that they can work as inhibitors to the cysteine protease that coronaviruses encode56-58. Experimental and clinical results proved combination to be effective against both SARS and MERS-CoV50,51,54,59. Hence, the combination of lopinavir and ritonavir was repurposed against the SARS-CoV-2 (NCT04252885) as well. However, only a small improvement was noticed in mild cases49 whereas nothing remarkable could be extracted in the severe ones60. Earlier study in China found faster clearance of SARS-CoV-2 by PCR and faster improvement of chest computed tomography. A randomized, open-label clinical trial comparing LPV/r versus placebo in patients with severe COVID-19 found no statistically significant difference in time to clinical improvement or 28-day mortality. In July, WHO announced to discontinue lopinavir/ritonavir treatment for COVID-19, since clinical trial results showed that hydroxychloroquine and lopinavir/ritonavir produce little or no reduction in the mortality of hospitalized COVID-19 patients when compared to standard of care.A popular drug combination of lopinavir and ritonavir against human immunodeficiency virus (HIV), which is basically a facilitator of protease inhibition in the virus itself, already made its mark as a successful therapeutic agent61. As for the case of SARS-CoV-2, it has shown its ability to inhibit the replication of this virus as well by interrupting the glycosylation of its receptor protein-ACE262. This claim has been supported by several in-vitro clinical trials of the drug that saw a significant reduction in the copy numbers of SARS-CoV-263. Clinical trials in China concluded that hydroxychloroquine is only effective against COVID-19 associated pneumonia, not against the virus specifically31. A non-randomized clinical trial in France gave out a somewhat optimistic result when hydroxychloroquine was combined with azithromycin 64. However, the WHO decided on July 15, 2020 to halt clinical trials of hydroxychloroquine as a potential treatment for hospitalized COVID-19 patients65. When compared with the standard of care in the treatment of hospitalized COVID-19 patients, hydroxy-chloroquine did not result in the reduction of the mortality of the patients.Hydroxychloroquine, most famously known as an anti-malarial drug and an anti-immune agent operates by suppressing acidification of cellular endosome during the events of replication and infection66. It interrupts the endocytosis of influenza virus by preventing the fusion of viral body with endosome through targeting hemagglutinin of viral surface31. Arbidol is already approved in Russia and China for COVID-19 drug trials now as a single agent66. But in a comparative study, favipiravir turned out to be more effective than arbidol67. An in vitro study in China shows that arbidol inhibits SARS-CoV-2 infection whenever applied at a minimal concentration. Nowadays, a dose of (200 mg) arbidol is given three times per day not for more than 10 days to treat COVID-19. A randomized study was also conducted to determine the efficacy of arbidol in combination with recombinant human interferon-α2β to treat mild to moderate pneumonia due to COVID-1968. China awaits two phase IV drug trials of Arbidol , to provide a conclusive result by February 2021.Arbidol acts upon influenza viruses and arboviruses as an entry inhibitor31. In fact, rhACE2 is found to be able to obstruct SARS-CoV-2 replication by a factor of about 5,000 times maximum according to contemporary studies on embryonic cell-mediated organoids69. Applying rhACE2 has been reported to abate serum level of angiotensin 2 that diverts the substrate away from the receptor ACE; eventually intervening with activation of ACE2 as well to prevent ARDS (Acute Respiratory Distress Syndrome)70. In China, a study has been carried out to evaluate the biological and physiological role of rhACE2 NCT04287686) against COVID-19 and so it made to the list of potential drugs against SARS CoV-2 in terms of measurement of plasma level of angiotensin 1-731. A couple of other studies in Austria and Australia  are dealing with the final phase of angiotensin inhibitory drugs due to be published in two years.For an angiotensin receptor inhibitor, recombinant human angiotensin converting enzyme 2 (rhACE2) is now being recommended because of its ability to block S protein from binding to the host receptor ACE271. Studies also reported the successful use of thalidomide against H1N1-infected mice, as it facilitates production of pro-inflammatory cytokines and reduction of infiltration of inflammatory cells72. Recent emergence of thalidomide as an anti-inflammatory, anti-fibrotic and anti-angiogenic agent has put it in the discussion of being a repurposing drug against certain SARS-CoV-2 strains  predicting its immunomodulatory ability of reducing lung defect31.Thalidomide was used as a treatment plan against some of the severe inflammatory diseases such as Behcet’s disease and Crohn’s disease and it acts by decreasing synthesis of TNF-α31. Methylprednisolone is one of the potential drugs like thalidomide that can supposedly inactivate such unexpected immune reaction. Nowadays along with antibiotics, oseltamivir, and oxygen therapy methylprednisolone is being used to treat COVID-19 patients33. Several clinical trials are ongoing  to determine whether or not it’s safe and useable31.Pathogenesis of SARS-CoV-2 is supported not only by the direct damage it causes to the host, but also by the excessive immune response that the host cell offers73. While it has been used as an effective anti-viral drug, as of now it is being considered to be repurposing against COVID-1974. Chloroquine inhibits pH-dependent steps of the replication of many viruses that has already been quite extensively tested both in vitro and in vivo on different virus strains and recently, on SARS-CoV-2. Though treatment with chloroquine showed promising results, it also strongly differed in application between live animals and cell lines. The major finding was that even if chloroquine shows promising results on virus75 and cells, the in vivo application is not so promising75. China, South Korea and Italy allowed for experimental trials of chloroquine against SARS-CoV-276,77. Having a lower therapeutic index, chloroquine may often turn out to be toxic for the user78,79. FDA didn’t approve hydroxychloroquine and chloroquine under emergency use authorization (EUA)80. In short, no conclusive clinical trial has proved efficacy of the drug till now although research is still underway in Mexico , Egypt (NCT04353336), USA (NCT04349371), UK (NCT04303507) and many other countries.Chloroquine is an anti-malarial drug81. It blocks the receptor of angiotensin-2 from entering the cells and raising blood pressure. Losartan is being perceived as an antagonist, since it interferes with the substrate-ACE2 receptor interaction of SARS-CoV-282. However, according to a recent study, such medication for hypertension might end up inducing the host to produce more ACE2 instead and increasing susceptibility of the virus in the process83,84. Various studies are taking place across different phases of development on losartan including a phase IV study by Sharp Healthcare (NCT04340557) and a couple of phase II studies by University of Minnesota .Losartan is a widely used drug for treating hypertension and left ventricular hypertrophy (heart muscle enlargement) and kidney dysfunction in type-2 diabetes85. Few phase III studies are also being carried out in France solely on azithromycin . Gautret et al. reported a 100% viral clearance in nasopharyngeal swabs in their 6 patients whenever they were treated with both the drugs. The findings reported by Molina et al. stood in contrast with those reported by Gautret. They repeated the experiments and found 8 of 11 patients having remarkable comorbidities83.Azithromycin could reduce the severe lung inflammation caused by SARS-CoV-2 infection, through halting the production of cytokines, along with building immunity against other viruses. Azithromycin along with hydroxychloroquine was able to inhibit SARS-CoV2 replication in a clinical trial in France, however, the result was not reproducible when the antibiotic was administered alone83,86 and polycythemia vera (PCV) that occurs when there’s a lack of response to hydroxyurea87. It is a janus kinase inhibitor (JAK inhibitor) particularly involving JAK1 and JAK288. It was reported to cause faster improvement of the COVID-19 patients by Ruxolitinib administration but a phase II clinical trial failed to account this89. Incyte, a biopharmaceutical company, has initiated a phase III clinical trial to assess the safety and efficacy of the drug material (NCT04377620)90. Few other phase II and phase II / phase III clinical trials are focused on ruxolitinib in both America and Europe .Ruxolitinib is used to treat intermediate or severe myelofibrosis (bone marrow disorder)91. The anti-inflammatory properties of baricitinib inspired some groups to observe its effect in inflammation92. Oral administration of baricitinib could potentially reduce inflammation in COVID-19 associated ARDS93. National Institute of Allergy and Infectious Diseases (NIAID) launched a study on combination of remdesivir and baricitinib for a better anti-inflammatory outcome than remdesivir alone (NCT04401579)93. As for single studies, baricitinib is currently being researched in various clinical trial phases .Baricitinib is another anti-inflammatory drug approved to be used against rheumatoid arthritis (RA), as a janus kinase inhibitor (anti-JAK)94. A phase II study is being conducted on iNO in patients afflicted with ARDS resulted from SARS-CoV-2 infection95. A phase III study has also been approved by FDA for ensuring safety and efficacy of the drug in patients with COVID-19 needing supplemental oxygen before advancing to forced ventilation95. On March 20, 2020, FDA granted emergency expanded access allowing its iNO delivery system (INOpulse) to be immediately used for the treatment of COVID-19 (NCT04421508). However, more study results are needed to be evaluated  to determine the efficacy of iNO in treating COVID-19 patients.Nitric oxide ) produced by Mallinckrodt Pharmaceuticals Inc is known to reduce pulmonary hypertension and hypoxia by lessening ventilation support84. A study confirmed the ability of vitamin C to lessen death rate by 20% in patients with lung damage96. Another study in China showed zero death out of 50 intermediate patients treated with high doses of vitamin C. Progenbiome of USA has initiated a couple of phase II clinical trials on Vitamin-C  alongside other drugs. A phase III research on only Vitamin-C has also been brought under consideration in Sherbrooke University . However, the overall effect and outcome of vitamin C in treating COVID-19 alone or in combination are disputable.Vitamin C also known as ascorbic acid helps boost the immune system through its antioxidant properties and collagen synthesis. It is an effective and simple molecule without any side effects or cross-reaction with available COVID-19 drugs. Some hospitals have been reported to have prescribed high-dose of intravenous vitamin C for the treatment of 50 moderate to severe COVID-19 patients in China. The dose varied between 2 and 10 g per day over a period of 8 to 10 hours of IV (intravenous) infusion. The oxygenation index was improved and all the patients recovered97. Recently, dexamethasone proved to be the first life-saving drug among seriously ill COVID-19 patients. The study comprised of 2,100 candidates receiving dexamethasone compared with 4,300 people given standard care. Dexamethasone reduced death by one third for people on ventilation and reduced risk by one fifth for the patients needing oxygen. But the results have not yet been peer reviewed. Dexamethasone phase III and phase IV clinical trials to conclude in near future will be able to help create an extensive platform for further utilization of the drug .Dexamethasone is a corticosteroid used for different inflammation conditions and other diseases like arthritis, lupus, breathing disorders etc. A study in March 2020 concluded that an early dose of dexamethasone would reduce inflammation in COVID-19 associated ARDS and thus control mortality rate to a large extent suppressing ventilation tendency20 that targets the neuraminidase on the surface of influenza virus to inhibit the virus from entering human cells98,99. An initial clinical trial in Wuhan didn't show a success when using the drug for COVID-19 patients. Still, oseltamivir is being studied in a combination with chloroquine and favipiravir around the world. A phase III clinical trial on oseltamivir by Federal Task Force on Science and Technology in Pakistan (NCT04338698) is expected to provide a definitive take on the future of this particular drug.Oseltamivir is an already approved drug against influenza A and B20. It blocks neutrophils from transferring to inflammation sites and inhibits forming inflammasome complex blocking its activation100. Colchicine has been reported to reduce inflammation in the cardiac myocytes of patients with both COVID-19 and myopathies101. Several other studies are being conducted on colchicines, NCT04355143, NCT04322682) for cytokine storm20.Colchicine is an anti-inflammatory drug used for gout management along with treating other complications102. Through an unreliable source, it is also reported that the drug suppresses proinflammatory cytokines in peripheral blood mononuclear cells (PBMC) and IL-6 in vivo103. Nitazoxanide 500 mg is in phase IV clinical trials due to be concluded by the end of the current year .Nitazoxanide is an anti-viral drug inhibiting the expression of viral N protein, shown to have inhibitory effects against MERS-CoV in LLC-MK2 cells, along with several other coronaviruses, mouse hepatitis virus strain A59 (MHV-A59), human enteric corona virus 4408 (HECoV-4408) and bovine coronavirus strain L9 (BCoV-L9)104. It has been seen that blocking of nuclear export automatically disrupts the replication of SARS-CoV-2. With that in mind, selinexor is now being explored through phase I and phase II clinical trials, by leading health organizations like Norton Healthcare and Lehigh Valley Health Network. Currently, Karyopharm therapeutics is conducting a phase II clinical trial on the drug .Selinexor is an FDA approved drug in high doses, used for cancer conditions, such as relapsed multiple myeloma. Manufactured by Karyopharm Therapeutics Inc, selinexor is an oral selective inhibitor of nuclear export (SINE) in cells105.Methothrexate (MTX) is a drug dedicated to treat different cancer cases, such as breast, skin and lung cancer and to treat psoriasis and rheumatoid arthritis in lower doses. While it is still not known whether SARS-CoV-2 is susceptible to the drug or not, for those COVID-19 patients with rheumatoid arthritis as an additional condition it is recommended to stop their medication on MTX for a while until the complexity is resolved. A Brazilian research team collaborating with an Indian-based contract research organization has initiated a study on methotrexate nano-particles (NCT04352465) to treat COVID-19 by evaluating inflammatory responses in patients106.Tranexemic acid or TXA is a derivative of amino acid lysine helping blood coagulate. It carries antifibrinolytic property to reverse excessive blood loss from traumas and surgeries. One of the lesser known symptoms of COVID-19 is coagulopathy. University of Alabama researchers are conducting two phase II clinical trials on TXA , to figure out its ability in balancing the coagulation factors in COVID-19 patients33. TCM synthesized by local Chinese manufacturers claimed to have effect in combating infectious diseases such as COVID-19.Traditional Chinese Medicine (TCM) which uses phytotherapeutic formulations like teas, pills, powders or tinctures, and cultural components can be traced back 5000 years ago in Chinese medicine. These were already used for SARS-CoV infection as coadjuvant therapy with the enhancement of patient’s symptoms, increased oxyhemoglobin arterial saturation in 2002107. The first vaccine (Pfizer-BioNTech mRNA-based vaccine) just received emergency approval in December 2020 for use in USA and UK. Additional vaccines (such as the mRNA-based vaccine from Moderna) will follow. These are excellent news. However, it will take months to have the vaccines distributed worldwide, their long-term effects are hard to predict, and the possibility of future resistant mutations is a concern.With the rising cases of SARS-CoV-2 infection, it is apparent that COVID-19 is going to be prevailing for a long time and the battle against any virus can be ultimately won through an effective and safe vaccine108 by promoting a long term strategy against the virus39. Experts have warned of any shortcut in vaccine development due to public pressure which may elicit antibody-dependent enhancement, resulting in long term consequences109. In spite of these, we really cannot rule out the fact that production of vaccine is the most effective and viable alternative to combat an emerging pandemic, such as COVID-19. Many vaccine clinical trials are currently going across the globe, including a BCG vaccine , heat killed Mycobacterium vaccine  and MMR vaccine (NCT04357028). ChAdOx1 ncoV-19 (NCT04444674), recombinant nCoV-19 (NCT04313127) and inactivated nCoV, which are in different clinical phases now to develop host immunity . We are discussing several COVID-19 vaccines in clinical trials below.Vaccines can be a reliable therapeutic approach39,110. No virus was required to formulate the vaccine and platform technology made its production easier and safer for testing (NCT04283461)39,109. Elevated titer of neutralizing antibody was observed in convalescent serum in all the initial 45 candidates whenever 2 dosages were applied of that particular vaccine111. Moderna is very much hopeful that mRNA-1273 will be commercially available on the market soon. The study group published a preliminary report on July 14, 2020 of a phase I, dose-escalation, open-label clinical trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no clinical trial-limiting safety concerns were identified. These findings shed light of hope to the already COVID-19 stricken world.mRNA-1273 , developed by Moderna, an American biotech company in association with National Institute of Allergy and infectious disease (NIAID), has caught the scene for a while now. It is a synthetic mRNA which is surrounded by minute particles composed of lipids. Similar to the Pfizer-BioNTech vaccine , it is supposed to induce antiviral response in the injected cells against spike proteins of SARS CoV-2 (NCT04283461)34,112. The INO-4700 was administered successfully against MERS-S within a DNA vector and INO-4800 is now in clinical trials against SARS-CoV-2-S31. INO-4800 is transdermally applied to healthy candidates through the help of an electroporation device called Cellectra, to determine its immunological features111. Ease in purification and lower expense in production make it potentially preferable over other vaccine types39. In preclinical animal challenge study, INO-4800 provided full protection against SARS-CoV-2 replication in the lungs in mice. 94% of participants demonstrated overall immune responses at week 6 after two doses of INO-4800 in phase I clinical trial with 40 healthy volunteers. The vaccine elicited no serious adverse effects through week 8 with some grade I severity.INO-4800, a DNA vaccine developed by INOVIO Pharmaceuticals  is another genetic vaccine that utilizes the process of immune response against specific viruses. Such genetic vaccines do not involve risk of improper protein folding like the protein-based vaccines113 against viruses like Ebola virus114, Influenza A115 and MERS116. ChAdOx1 vaccine was designed by the University of Oxford in collaboration with AstraZeneca, based upon adenovirus vector against the spike protein S of SARS-CoV-2 (NCT04324606)39. ChAdOx1 vaccination prevented lung damage, indicating promising outcomes in the near future. The vaccine began phase I clinical trial in April. The University later went on to host two more clinical trials on ChAdOx, including one in collaboration with South Africa . With all these being said, if successful, ChAdOx is showing immense probability of being one of the most sustainable vaccines against COVID-19, although if the induced immunogenicity in host is propelled towards the vector genome rather than the transgenes, it might cause an unexpected failure in the vaccination process. Over 5,000 healthy volunteers began participating in Brazilian clinical trial of this vaccine. Oxford researchers have begun recruiting for the phase II/phase III clinical trial and planning to apply ChAdOx1 on children.ChAd vectors have already been established as safe and 100% efficient with single vaccination39. General nanoparticles-based vaccination includes oral and intranasal uptake, which can induce immunity on the mucosal surface, in addition to the systemic immune responses117. This indicates how these vaccines would be effective against respiratory viral infections, including SARS-CoV-239. An investigation was conducted to determine potency between nanoparticle (polyethylenimine) that elicited spike (S) protein of SARS-CoV and naked plasmid vector. Nanoparticle produced elevated level of spike (S) protein specific antibody over naked plasmid vector118. For that purpose, Novavax Inc. has taken the initiative of producing a vaccine based on nanoparticles using spike proteins of SARS-CoV-2 (NCT04368988)39. Another study is under clinical trial as of now evaluating mRNA-lipid nanoparticles-based vaccine previously successful against SARS and MERS-CoV (NCT04283461). Many additional vaccines are now in clinical trials and expected to be approved for use in the near future.Nanoparticles-based vaccines are produced through encapsulation by adjoining with antigenic epitopes mimicking viral attacksFigure 4B). France and Spain come next with 62 and 56 ongoing clinical drug trials respectively. Among other most affected nations, Italy has 41 drug trials ongoing, whereas Canada holds about 48 clinical trials attempting to battle COVID-19 (Table 4). It can be derived that North American countries have an upper hand in drug research, whilst other than China, the Asian countries are lagging quite behind. European countries are also providing a decent and above average service in developing drugs. Most of the drug trials are being sponsored by various universities and organizations, while multiple pharmaceutical giants are also investing in a significant number of clinical trials across the globe. There are few other government sponsored organizations, such as NIH and FDA investing in a number of clinical trials.The United States is dominating the ranking for the number of clinical trials for the highest number of drugs (347). As far as drug research is concerned, in China, they have 65 drug trials ongoing as of now .Each of these tested drugs is constantly going through clinical trials and errors to be finally selected for approval. Most of the drug trials are in developmental phase II and III (335 and 195 respectively). 61 drug trials are in the final phase of drug development, while 50 others have no designation at all as in what phase they are in (Table 5). However, gaining a positive result out of them still asks for absolute confirmation of the feasibility of the drugs from clinical trials on population. That may lead to some of the drugs taking up to 2030 to be finally prescribed as safe. Since the majority of the drugs are currently nearing to the final phase of development, it may be expected that within late 2021, sustainable drug products will be well constructed and readily available or will lay out some standard and similar protocols for an effective drug at the least.There is no telling as to when a suitable drug may be advertised to cure COVID-19. But as it is estimated, among the 876 clinical drug trials, over half of them may be well predicted by the end of 2020 (Worldwide researchers and physicians are doing their best to extract more information about the virus, so that they can figure out effective ways to completely eliminate the lethal pandemic, which has become a threat for human health worldwide. In such emergence of the pandemic, drug repurposing is being considered to be a quicker way to show rapid and effective response. This study tried to systematically address the current scenarios of the clinical trials of the repurposed drugs. Numerous repurposing drug candidates are in clinical trial in many countries simultaneously. Several biological treatments, including convalescent plasma, recombinant interferon, mesenchymal stem cell, antibodies, and the use of the NK cells are undergoing clinical trials and has already exhibited promising results. Among chemically derived drugs, remdesivir was the first treatment for COVID-19 to receive FDA approval. Dexamethasone proved to be the first life-saving drug among seriously ill COVID-19 patients. For hydroxychloroquine, despite showing some promising results at first, clinical trials were later halted at WHO’s recommendation. Although further investigations are needed to be carried out, there is a high probability that within a short period of time, some of these various treatment plans in clinical trials will be approved in terms of safety and efficacy and will be available in the global market at lower cost. Such efforts may facilitate the discovery of new classes of medicines as well. While attempts to synthesize a novel treatment plan continue from the scientific community, the repurposing treatments in clinical trials are bound to provide a reliable ground for withholding the disease until that novelty is achieved. In addition, some of the novel vaccine candidates in clinical trials are already listed here and many more are in the pipeline to undergo clinical trials soon. Such a detailed view of drug and vaccine candidates is expected to assist in and add a new dimension to the ongoing process of developing therapeutic and prevention options against COVID-19, on a huge global platform.


End of April 2020, French clinicians observed an increase in cases presenting with paediatric inflammatory multisystem syndrome (PIMS). Nationwide surveillance was set up and demonstrated temporospatial association with the coronavirus disease (COVID-19) epidemic for 156 reported cases as at 17 May: 108 were classified as confirmed (n = 79), probable (n = 16) or possible (n = 13) post-COVID-19 PIMS cases. A continuum of clinical features from Kawasaki-like disease to myocarditis was observed, requiring intensive care in 67% of cases. On 28 April 2020, French clinicians alerted the French Public Health Agency about an abnormal increase in cases of Kawasaki-like disease (KLD) and myocarditis in children requiring critical care support that occurred during of the ongoing coronavirus disease COVID-19) epidemic in France. Concomitantly, Riphagen et al. reported eight children displaying characteristics of hyperinflammatory shock, KLD or toxic shock syndrome [9 epidemiTo investigate this emerging inflammatory disease in children, now named paediatric inflammatory multisystem syndrome (PIMS) or multisystem inflammatory syndrome in children (MIS-C), a nationwide surveillance was launched on 30 April, coordinated by the French Public Health Agency and French paediatric scientific societies. All French paediatric departments were asked to report retrospectively and prospectively all cases of this hyperinflammatory syndrome diagnosed since 1 March to Santé Publique France. The objectives of this surveillance were to estimate the burden of PIMS in France, to describe the spatial and temporal dynamics of this emergence in order to investigate its link with the COVID-19 epidemic.A reporting form was developed which included age of the patient, results of either RT-PCR or serology for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), main clinical features , myocarditis or KLD), type of wards ) and, for children admitted to ICU, type of care required  and if relevant, occurrence of death. No follow-up of the child’s condition was planned in this initial data collection. Whenever either the PCR or the serology was noted as pending, clinicians were subsequently asked by email to update the questionnaire a few days after initial notification.Based on the main clinical features and on the available information regarding SARS-CoV-2 status, cases were classified into four categories, according to their link with COVID-19:• Confirmed/proven cases of SARS-CoV-2-related PIMS (CoV-PIMS) were children presenting with one or more of the following symptoms: seritis, characteristics of MAS, myocarditis and/or KLD and a positive SARS-CoV-2 RT-PCR or serology;• Probable CoV-PIMS cases were children presenting with any of the above clinical features and either a direct epidemiological link with a confirmed COVID-19 case or a chest computed tomography scan favouring the diagnosis of COVID-19;• Possible CoV-PIMS cases were children presenting with at least two of the above clinical features with pending or not performed PCR and serology;• Non-CoV PIMS cases were children with both negative PCR and serology or with pending or not performed PCR and serology and presenting with only one of the above clinical features.We compared the characteristics of the non-CoV PIMS and CoV-PIMS populations using Mann and Whitney test.Supplementary Table [The main analysis for CoV-PIMS was performed on possible, probable and confirmed cases only. A comparison of our own case definition with the case definitions from the World Health Organization (WHO), the United States Centers for Disease Control and Prevention (US CDC) and the Royal College of Paediatrics and Child Health (RCPCH) are reported in the ry Table -5.By the end of week 20 (17 May 2020), a total of 156 cases had been notified, 79 classified as confirmed, 16 as probable and 13 as possible CoV-PIMS cases. The 48 remaining cases were ruled out based on our case definition .The epidemic curve of the 108 analysed cases revealed a sharp increase in incidence after 13 April, culminating in week 18, 4–5 weeks after the peak of the COVID-19 epidemic in France and decreasing thereafter . The geoAge distribution showed a median of 8 years and an interquartile range of 5–11 years . The CoVThis study is, to date, the largest series of published PIMS cases, with more than 100 cases. It supports a causal relationship between SARS-CoV-2 infection and PIMS: 95 of the 156 notified cases were confirmed or probable post-COVID cases. Among the 48 excluded cases, 39 presented with KLD symptoms, probably reflecting the classical Kawasaki disease. Our case definition differed slightly from those proposed later on by the WHO, the RCPCH and the US CDC, mainly because we included as a possible case a patient with a pending or not performed diagnosis of SARS-CoV-2 infections. However, we believe that having classified them as possible PIMS cases reflects the actual likelihood of those cases being real PMS cases. Moreover, possible cases only represented 12% of all cases kept in the analysis and their temporal distribution as well as their age distribution and clinical features (data not shown) did not differ from those of probable and confirmed cases. The significant differences between the CoV2-PIMS and non-CoV2 PIMS cases regarding age distribution and main manifestation support a correct classification. We also highlight that further clinical reporting on all manifestations is required to improve the case definition and disease description. The epidemic curve of the PIMS cases followed that of COVID-19 with a lag time of 4–5 weeks, supporting the hypothesis of PIMS being a post-infectious manifestation. The geographical distribution of the PIMS cases also correlated with that of the COVID-19 cases. The almost simultaneous detection of PIMS cases in three other places heavily affected by the SARS-CoV-2 epidemic  , furtherOur study gives some insight into the actual risk of PIMS in children with COVID-19. Indeed, with the help of all concerned learned societies, we were able to set up a specific emergency notification system. We believe that the rarity and severity of the disease with frequent ICU admission, in a context of large media coverage of this new syndrome, has most probably led to a high notification rate. In the absence of specific routine Kawasaki disease surveillance, we were unable to compare the number of notified PIMS cases classified as non-CoV PIMS cases with historical classical Kawasaki disease background rates.Coronaviruses have previously been reported as a possible trigger of classical Kawasaki disease  but reprIn our report, 73% of patients required vasopressor/inotrope support in the ICU and one case was fatal. The European Centre for Disease Prevention and Control (ECDC) Rapid Risk Assessment from 15 May  identifiFrench surveillance data confirm the signal of the emergence of an inflammatory multisystem syndrome associated with SARS-CoV-2 infection in children. The actual risk of this disease is difficult to estimate, as reliable data on the incidence of COVID-19 infections in children are not yet available. COVID-19 cases in children younger than 15 years reported to The European Surveillance System (TESSy) represent only 2.1% of all laboratory-confirmed cases. Under the conservative estimate of no more than only 5% of French children under 15 years having been infected with SARS-CoV-2, the risk of PIMS, based on confirmed, probable and possible cases would be fewer than two per 10,000 children. In the short term, the risk of new cases of COVID- PIMS is likely to be very low in France, given the low circulation of the virus in France in the past few weeks. More data on this new syndrome will be collected through a research protocol that is currently being implemented. Countries with current high incidence of COVID-19 in the general population should consider this rare but severe delayed syndrome in children.


To document the experiences of converting a general hospital to a coronavirus disease 2019 (COVID-19) designated hospital during an outbreak in Daegu, Republic of Korea.The hospital management formed an emergency task force team, whose role was to organize the COVID-19 hospital. The task force used different collaborative channels to redistribute resources and expertise to the hospital. Leading doctors from the departments of infectious diseases, critical care and pulmonology developed standardized guidelines for treatment coherence. Nurses from the infection control team provided regular training on donning and doffing of personal protective equipment and basic safety measures.Keimyung University Daegu Dongsan hospital became a red zone hospital for COVID-19 patients on 21 February 2020. As of 29 June 2020, 1048 COVID-19 patients had been admitted to the hospital, of which 22 patients died and five patients were still being treated in the recovery ward. A total of 906 health-care personnel worked in the designated hospital, of whom 402 were regular hospital staff and 504 were dispatched health-care workers. Of these health-care workers, only one dispatched nurse acquired COVID-19. On June 15, the hospital management and Daegu city government decided to reconvert the main building to a general hospital for non-COVID-19 patients, while keeping the additional negative pressure rooms available, in case of resurgence of the disease.Centralized coordination in frontline hospital operation, staff management, and patient treatment and placement allowed for successful pooling and utilization of medical resources and manpower during the COVID-19 outbreak. Such health crises call for hospitals and other health-care facilities to develop strategies to manage unprecedented numbers of patients while competing for a finite set of resources.As of 29 June 2020, the country had reported 12 757 confirmed COVID-19 cases (including 1551 imported cases).The first confirmed COVID-19 case was reported on 20 January 2020.To respond to the outbreak and improve patient care, Daegu city government and the hospital management agreed to convert Keimyung University Daegu Dongsan Hospital to a COVID-19 designated hospital. Here we describe our experiences in anticipating, absorbing and adapting to an increase in the surge of patients during the COVID-19 outbreak.The private Keimyung University Dongsan Medical Center has three hospitals, of which two are located in Daegu: the tertiary hospital Keimyung University Dongsan Hospital with 992 beds and secondary level Daegu Dongsan Hospital with almost 1000 beds capacity, but only 216 beds in use before the COVID-19 outbreak.At the beginning of the outbreak, the policy in the country was to hospitalize all confirmed COVID-19 cases. However, on 21 February 2020, the accumulated number of patients in Daegu was 59, yet only 15 patients were able to be hospitalized due to the limited number of negative pressure rooms in the hospitals. To ensure that all COVID-19 patients could be admitted to a hospital, the Daegu city government agreed with the hospital management that the Daegu Dongsan Hospital should be the designated COVID-19 hospital in the city, since this hospital had a larger plot area and was easier to transform. The non-COVID-19 patients in Daegu Dongsan Hospital were therefore transferred to Keimyung University Dongsan Hospital.The management of Daegu Dongsan Hospital focused all its resources and expertise needed for COVID-19 patient care. The two hospitals established a joint emergency task force team, which consisted of leading staff members in the divisions of medicine, infection control, nursing, laboratory medicine, radiology, administration, facilities, logistics, nutrition and public relations. To enable swift communication and decision-making, the emergency task force team resided in the designated hospital’s annex building. A daily face-to-face meeting allowed the head of each department to actively discuss different topics of patient care, staffing, medical supplies and issues that need to be resolved.To reduce confusion in patient care, the heads of the department of infectious diseases, critical care and pulmonology had the ultimate authority. Doctors of different specialties participated in the COVID-19 patient care and they used group chats in the instant messaging application KakaoTalk for smartphones to discuss patient treatment in real time. The physician team, which included doctors from infectious disease, pulmonology, radiology and laboratory medicine, managed all areas of diagnosis and treatment of COVID-19 and infection control in the hospital. The task force assigned nurses to support the physician team. For example, the nurses managed the inpatient list and daily COVID-19 polymerase chain reaction (PCR) testing list, and reported the inpatient list and patients who had two consecutive negative PCR results to the government.Given the large number of patients but limited number of beds and negative pressure rooms, the task force decided to convert the entire main building of the hospital to a red zone on 21 February. With help from key health-care workers, primarily physicians of infectious diseases, who had experience in patient management and infection prevention and control of the Middle East respiratory syndrome, the hospital was transformed in one day. These key health-care workers managed the overall process to convert the main building to a red zone and suggested separated routes for medical staff and patients. Only employees wearing personal protective equipment could enter the main building through the entrance on the first floor, while COVID-19 patients entered the building through an entrance on the third floor. All other entrances were closed. Separate elevators were used for patients and staff, and line stickers were put on the floor to guide the route for patients and staff. Medical personnel could not enter the red zone without putting on personal protective equipment in Anteroom A . All general wards, located on the fifth to eighth floor in the hospital, were now used for COVID-19 patients. Bed-ridden or elderly patients as well as patients with severe pneumonia were placed on the fifth floor so that they could be moved quickly if needed to the intensive care unit, also located on the fifth floor. At first, only three negative pressure rooms were available in the intensive care unit. We expanded the number of beds in the unit to 20 beds. At first, there was no time for creating individual negative pressure rooms in the intensive care unit, but we created a station surrounded by a dividing glass wall in the centre of the unit, allowing medical staff to monitor patients inside the station.To minimize the time health-care workers spent in the hospital wards and to potentially reduce the infection risk, we placed smartphones in each ward. These devices were used for video consultations before ward rounds to check patients’ conditions.To separate recovering patients from those who were more sick, the task force created a separate recovery ward in an additional hospital building (previously used as a research building).Expensive and hard-to-obtain medical devices needed for the set-up of new intensive care units, such as extracorporeal membrane oxygenation and mechanical ventilators, were lent by other hospitals or were purchased with funding from nongovernmental organizations.At the beginning of April, we constructed six additional negative pressure rooms in the general wards to expand the hospital’s capacity to isolate suspected COVID-19 patients who may require treatment. Before the construction, we transferred the COVID-19 patients on the relevant floor to other floors within the main building or to the recovery ward. After ventilating the area for 24 hours, we started the construction of the negative pressure rooms. The entire construction took 10 days and ended on 14 April 2020. Separate anterooms for donning and doffing of personal protective equipment were built, and interlocking doors and portable negative pressure equipment were installed.All health-care workers in contact with confirmed COVID-19 patients were instructed to wear coveralls, N95 mask, goggles or face shield and double gloves. When treating patients for more than 3–4 hours or in situations where aerosols could be generated (for example during intubation or suction), health-care workers wore a powered air purifying respirator. All medical personnel wore such respirators constantly while working in spaces with high probability of aerosol generation, such as in the intensive care units. Health-care workers discarded coveralls, N95 masks and gloves after use. Due to a shortage in supply of goggles and powered air purifying respirators, health-care workers reused them after the equipment had been sterilized. After the first use, powered air purifying respirators were first wiped with alcohol and then with a benzalkonium chloride tissue. After 1–2 weeks of use, we used ethylene oxide gas to sterilize them. We discarded reused powered air purifying respirators after they been sterilized with ethylene oxide gas once or twice, because safe performance of the respirator could not be guaranteed. We sterilized the goggles by cleaning them with 70% (vol./vol.) ethanol and wiping with dry tissues, and then disinfected them with ethylene oxide gas.By having two separate anterooms , one forAll health-care workers received one KF94 or surgical mask per day to wear at all times when they resided in the clean zone.We prioritized more experienced health-care workers and those with experience in other high-consequence pathogens to improve patient care and support less experienced health-care workers at the beginning of this outbreak.In the early stages of the running of the COVID-19 hospital, the ordinary workforce was able to provide treatment to all COVID-19 patients. However, as the number of patients, beds and intensive care units increased, additional health-care workers were needed, not only to fill the gap in staffing but also to relieve fatigued personnel. Doctors and nurses from other parts of the country were rapidly dispatched to the hospital through different medical societies. First, public hospital doctors and nurses, military doctors, public health doctors and nurse officers were dispatched. Then, civilian nurses recruited from the health ministry and civilian doctors who were volunteering participated in COVID-19 patient treatment. The Medical Association, the Society of Critical Care Medicine and the Nurses Association of the Republic of Korea also helped to recruit volunteers. The national government covered most of housing fees, daily expenses, hazard pay and other costs associated with dispatchment of workforce. The medical and humanitarian assistance nongovernmental organization, Global Care, also partly supported the dispatchment.To ensure safety of all health-care workers and to prevent nosocomial infection, nurses from the infection control team provided regular training on donning and doffing of personal protective equipment and basic safety measures, such as how to prevent virus exposure and what to do if one is exposed. The training sessions, which were given on-site at least twice every day, lasted about one hour. Before the hands-on training, participants were given instructions on wearing and removing of personal protective equipment. If the trainer deemed a participant to be unskilled, the participant was re-trained until a satisfactory level was reached. During training, we also provided N95 mask fit testing so individuals could select the most suitable N95 mask. We enabled regular check-ups of the masks by constructing an N95 mask fit test booth near Anteroom A where personal protective equipment was put on.The emergency task force team instructed all health-care personnel not to eat face-to-face or communicate with one another during meals. In staff cafeteria, distances between all chairs were doubled and seats were rearranged so that staff members were not facing each other.To reduce confusion in patient treatment and negative outcomes, leading doctors from the departments of infectious diseases, critical care and pulmonology developed standardized guidelines for treatment coherence. They developed two treatment guidelines: one for patients with mild symptoms  and one for patients who required critical care . To ensure standardized care was given to all patients, the leading doctors announced the guidelines on the bulletin board and also shared in group chats in an instant messaging app. This approach reflects the recommendationTo help with patient placement in the hospital, we developed a novel scoring system to predict progression to severe pneumonia in patients with COVID-19. The scoring system contained four independent predictive factors for progression  and each factor’s score was based on its regression coefficient, which we obtained through a multivariate logistic regression analysis. The risk score is the sum of the factor scores, and a patient’s risk score could range from 0 to 20 points . We consBox 1< 50 years: 0 points 50–59 years: 4 points60–69 years: 5 points70–79 years: 7 points> 79 years: 10 points< 1.4 mg/dL: 0 points≥ 1.4 mg/dL: 3 points< 500 U/L: 0 points500–700 U/L: 2 points> 700 U/L: 4 points< 13.3 g/dL: 0 points≥ 13.3 g/dL: 3 pointsAs the number of newly confirmed COVID-19 patients in Daegu declined and there were no more COVID-19 patients needing intensive care, the hospital management decided to reconvert the main building to a general hospital on 15 June 2020. To prepare for a new surge of COVID-19 cases, we maintained 154 beds in the recovery ward for COVID-19 patients presenting with mild symptoms. After the Daegu Dongsan Hospital was designated as a COVID-19 hospital, its total capacity increased from 216 beds and five wards, including one intensive care unit, to 465 beds and 10 wards, including two intensive care units . As of 2A total of 906 health-care personnel worked in the designated hospital, of whom 402 were regular hospital staff and 504 were dispatched health-care workers. Of these health-care workers, only one dispatched nurse acquired COVID-19.On 21 May, the remaining COVID-19 patients hospitalized in the main building were transferred to the recovery ward. On June 15, the hospital management and Daegu city government decided to reconvert the main building to a general hospital for non-COVID-19 patients, while keeping the negative pressure rooms, three in the intensive care unit and six in the general ward.Here we describe how a general hospital in the epicentre of a COVID-19 outbreak was transformed into a red zone hospital. Converting the entire hospital to a red zone ensured both isolation and care for COVID-19 patients as well as protection of health-care workers.While city government and hospital management undertook many measures in response to the surge in cases, we believe three measures in particular played a pivotal role in controlling the outbreak and dealing with resource and personnel constraints. First, the decision to develop and operate a COVID-19-specialized red zone hospital was an emergency strategy that allowed efficient use of already limited personal protective equipment and medical personnel. In addition, the conversion enabled us to easily expand specific bed capacity. Second, involving experienced staff in setting up the emergency response system was key in providing well-orchestrated care provision and reducing avoidable work-related burden. Their leading roles and experience helped other staff members new to the infectious disease control field. Third, the coordinated approach taken by the government and the hospital allowed for pooling of much needed resources in the COVID-19 hospital and helped to preserve normal functions of other hospitals in the city. Patients in other hospitals diagnosed with COVID-19 were immediately transferred to the designated COVID-19 hospital. Despite the high number of health-care workers working at the hospital, only one acquired COVID-19. We believe that the thorough training on the use of personal protective equipment, the adequate supply of such equipment, the additional workforce and the social distancing rules for staff contributed to this positive outcome.Making the hospital a COVID-19 designated hospital guaranteed an adequate supply of personal protective equipment, since the reconverted hospital received direct and prioritized assistance from the central government and Daegu city government. In addition, other entities, including the national Center for Disease Control and Prevention, companies and citizens, donated personal protective equipment to the hospital. Therefore, all health-care workers in contact with confirmed COVID-19 patients were able to wear personal protective equipment at all times. As the COVID-19 outbreak continued, we noted that health-care workers began to experience greater physical and mental fatigue. Therefore, placing empowered staff leaders at the designated hospital was important to boost morale and make workers feel valued, as well as protecting the health-care workforce. Another challenge was the non-medical personnel, such as cleaners and people distributing the meals, who were not familiar with infectious diseases and infection control. Without adequate training they posed a higher risk of virus exposure and nosocomial infection, which could lead to a serious personnel shortage. We therefore also provided training for them and gave them feedback.We hope our experiences and lessons learnt while converting a hospital to a designated COVID-19 hospital will be useful for public health officials in other countries experiencing similar situations.


Sweden revised their cervical cancer screening program in 2017 to include cytology-based screening for women aged 23–29 years and primary human papillomavirus (HPV) testing for women aged 30–64 years; however, alternative strategies may be preferred. To inform cervical cancer prevention policies for unvaccinated women, we evaluated the cost-effectiveness of alternative screening strategies, including the current Swedish guidelines.We adapted a mathematical simulation model of HPV and cervical cancer to the Swedish context using primary epidemiologic data. We compared the cost-effectiveness of alternative screening strategies that varied by the age to start screening, the age to switch from cytology to HPV testing, HPV strategies not preceded by cytology, screening frequency, and management of HPV-positive/cytology-negative women.We found that the current Swedish guidelines were more costly and less effective than alternative primary HPV-based strategies. All cost-efficient strategies involved primary HPV testing not preceded by cytology for younger women. Given a cost-effectiveness threshold of €85,619 per quality-adjusted life year gained, the optimal strategy involved 5-yearly primary HPV-based screening for women aged 23–50 years and 10-yearly HPV-based screening for women older than age 50 years.Primary screening based on HPV alone may be considered for unvaccinated women for those countries with similar HPV burdens. Cytology-based cervical cancer screening programs have significantly reduced cervical cancer incidence and mortality in most high income countries , 2. AdvaIn Sweden, national cytology-based screening began in 1973 . The scrThe cost-effectiveness of cervical cancer screening using primary HPV testing has been previously evaluated in other settings ; howeverFor unvaccinated populations, primary HPV testing for these women may be considered resource intensive, potentially resulting in more colposcopies due to the higher prevalence of HPV in younger women . HoweverTo inform policy-making for cervical cancer screening in Sweden together with countries with similar HPV epidemiologic profiles, our objective was to assess the cost-effectiveness of cervical screening strategies for women not vaccinated against HPV infections within the Swedish context, including an extensive evaluation of primary HPV-based strategies for younger women.We adapted an existing mathematical model to reflect the natural history of HPV-induced cervical cancer in Sweden in order to project the health and economic outcomes associated with alternative scenarios of screening. For each screening strategy, we calculated the incremental costs and the incremental health benefits of a strategy compared to the next least costly strategy. We removed strategies that were more costly and less effective (strongly dominated) and strategies that were less costly and less cost-effective (weakly dominated). Effectiveness was represented by quality-adjusted life-expectancy (QALE), which is measured in terms of quality-adjusted life-years (QALYs), incorporating disutility due to cervical cancer . Life exThe previously developed microsimulation model  has beenWe adapted the model to reflect HPV-induced cervical cancer in Sweden using a likelihood calibration approach. The model was run over a grid of input parameters to produce simulation predictions, and then those predictions were compared with the ‘observed’ calibration targets to calculate a log-likelihood. The observed calibration targets included Swedish cancer incidence in a pre-screening population, Swedish age-specific HPV prevalence, HPV type distribution in high grade CIN and in cervical cancer. The input parameter set with the highest log-likelihood was taken as the maximum likelihood estimator and we selected the fifty most likely parameter sets using a likelihood ratio test. We used the 50 best-fitting parameter sets to reflect uncertainty in the underlying natural history of disease. Following the calibration, we validated the model to the Swedish context see the .The current guidelines in Sweden  recommend triennial cytology-based screening starting at age 23 years and switching at age 30 years to triennial HPV-based testing up to age 50 years, and reducing the screening interval to every seventh year until age 64 years  was assumed to be 100 percent in our base case analysis. Due to the growing literature on HPV-negative cervical cancer tumours –38, we vBoth the current (HPV-based after age 30 years) and previous  screening guidelines in Sweden were more costly and less effective than alternative screening strategies . The preGiven the Swedish cost-effectiveness threshold of €85,619 per QALY gained, the optimal strategy involved primary HPV testing starting at age 23 years with 5-yearly screening intervals until age 50 years, followed by 10-yearly screening until an exit test after age 60 years . The optSimilar to when using the cost per QALY gained efficiency metric, all efficient strategies involved primary HPV testing when reporting outcomes of colposcopies and QALEs , Table 3Primary HPV-based strategies at 5-yearly intervals starting at age 23 years remained optimal across all sensitivity analyses, but the optimal screening frequency for women aged 50 years and older as well as the wait-time prior to repeat testing for HPV positive, cytology negative women varied across sensitivity analyses , we found that the strategy involving 5-yearly screening with primary HPV starting at age 23, 7-yearly screening from age 50, and 24 months follow-up time for HPV-positive, cytology-negative women was consistently projected to be on the efficiency frontier in 94 percent of the parameter sets , and provides more health benefit at a lower cost. Note that introducing self-sampling, as a complement to office-based collection, and a reduction in costs due to testing at scale may further improve the cost-effectiveness of primary HPV testing.In our sensitivity analyses, primary HPV testing for all ages remained consistently more effective and less costly, the optimal start age remained at 23 years, and 5-yearly screening intervals for women under 50 remained optimal. Assuming either 90 percent sensitivity for HPV tests, or changing compliance or cost assumptions resulted in a strategy that reduced the screening interval to seven years for women over age 50 years compared to the optimal strategy identified in the base case analysis. Importantly, the optimal strategy from the base case analysis was identified as cost-efficient in 36 percent of the parameter sets, while the corresponding strategy with seven-year intervals for women over 50 years of age was on the efficiency frontier for 94% of the parameter sets.Overtreatment and unnecessary colposcopies are a potential concern when using primary HPV testing for women less than age 30 years. When using colposcopy as an outcome, we found that primary HPV screening alone continued to dominate the other strategies. An important difference compared to the cost-effectiveness analysis was that the majority of the strategies on the colposcopy frontier involved waiting 36 months for HPV-positive and cytology negative women rather than 24 months. There is, however, a trade-off between follow-up time for colposcopy and effectiveness, where longer follow-up intervals for colposcopy may reduce resource use and costs by allowing for HPV to spontaneously clear, while possibly leading to disease progression and poorer outcomes .The cost-effectiveness of primary HPV screening in women under 30 years of age may reflect country-specific variations in HPV prevalence, which in Sweden is lower compared to Denmark and Norway . HoweverA strong advantage of our modelling approach is that we calibrated the model to detailed, linked health and population registers from Sweden. Using the calibrated model, we were able to validate the model predictions with data that were not used to inform the model inputs; from the validation, we found strong consistency with observed Swedish data for contemporary cervical cancer incidence rates Click here for additional data file.S1 Material(ZIP)Click here for additional data file.