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Advances in the possible treatment of COVID-19: A review
Abstract
The emergence of the global pandemic caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has put a challenge to identify or derive the therapeutics for its prevention and treatment. Despite the unprecedented advances in the modern medicinal system, currently, there are no proven effective therapies. However, rapid research on SARS-CoV-2 epidemiology help unveiling some new targets for potential drug therapies. Many drugs have been screened, and even their clinical trials are going on at an exceptional pace. Amongst these RNA-dependent RNA polymerase inhibitors (favipiravir and remdesivir) and steroids especially dexamethasone showed promising effects. The biological agents like tocilizumab, interferons, and convalescent plasma prove to be beneficial in viral clearance. Moreover, many immunomodulatory and viral S protein targeting vaccines have their ongoing clinical trials. The establishment of various in vitro and in vivo models for preclinical studies can additionally help the current research. The volume and the pace of the clinical trials launched to evaluate the safety and efficacy of various agents against coronavirus disease 2019 (COVID-19) reflect the need for high-quality evidence for various therapies to be practiced by clinicians. This study aims to sum up all the current advances in the global medicinal system against the COVID-19.
... It is an Adenosine Triphosphate (ATP) analogue and it is a prodrug of Remdesivir triphosphate (RDV-TP) that acts as an RNA-dependent RNA polymerase inhibitor that inhibits the replication of the virus. After entry into the host cell, Remdesivir undergoes cleavage to form the adenosine monophosphate analogue and undergoes phosphorylation giving rise to RDV-TP which resembles ATP [52]. There is competition between RDV-TP and ATP, and RDV-TP gets incorporated into the growing chain thereby causing premature termination of viral RNA transcription [53]. ...
... It is seen to inhibit the RNA-dependent RNA poly- merase. The possible mechanism of the activity of this drug is that it gets incorporated into the nascent viral RNA or may bind to conserved polymerase domains [52]. As a result, the process of replication and transcription of the viral genetic material is stopped. ...
... Therefore, by targeting IL-6 with Tocilizumab this symptom could be overcome and could aid in inhibiting the progress of the disease. This is generally the suggested treatment when there are extensive lung lesions observed in the patient [52]. ...
SARS-CoV-2 infection, commonly called COVID-19, has taken a jump from being rarely talked about to becoming a household name. Making it to history as the 5th global pandemic, this public health crisis has taken millions of lives all over the world. Right from the identification of patient zero, the pandemic has unfolded in waves of infection, triggering a domino effect that has impacted all aspects of life. Global efforts have been underway to combat this pandemic and minimize its repercussions, resulting in the development of efficient vaccines and drugs to treat the disease and control the spread of infection. However, making the benefits of these efforts available to everyone and walking the path towards the end of the pandemic remains a challenge. Keeping this in view, this review intends to present a summary of the sequential development of the pandemic, the recent advancements in the field of diagnostics and treatment, and the challenges that continue to remain in overcoming this public health crisis. It can be understood that the task of controlling and managing the impact of such a massive pandemic goes well beyond the boundaries of what present-day technology and advancements in the field of medicine and health care can offer. A collaborative and integrative approach between academic, scientific, social, and economic factors, along with close supervision and reinforcement of the current public safety protocols, can help to ensure a better management strategy to control the progression of COVID-19.
Graphical Abstract
... Recommendations were obtained from experts, namely Covid-19 self-healing patients who managed to recover. However, the healing rate of each expert is so different that it is difficult to get the best and most effective self-healing recommendations (Chibber, 2020;Hoffman, 2021). Information enrichment with crowdsourcing can combine various recommendations from experts to get the best recommendations. ...
... Individuals who consume well will have a more robust immune system and reduce the risk of infection. (Chibber, 2020) summarizes potential therapies for dealing with COVID-19 in China. Traditional Chinese medicines such as Lopinavir, Arbidol, Favipiravir, Tocilizumab, etc., are recommended with certain doses (Chibber, 2020). ...
... (Chibber, 2020) summarizes potential therapies for dealing with COVID-19 in China. Traditional Chinese medicines such as Lopinavir, Arbidol, Favipiravir, Tocilizumab, etc., are recommended with certain doses (Chibber, 2020). Other factors, such as the patient's efforts not to panic, have also been analyzed (Ali and Alharbi, 2020). ...
The global emergency caused by the COVID-19 pandemic does not yet have a registered drug. Many studies suggest strengthening the immune system in the human body as an alternative solution to treating COVID-19 before the discovery of drugs. This study reports on various types of potential treatments and factors associated with the immune response to the virus. The analysis shows that the effectiveness of the treatment depends on the current preferences of the COVID-19 patient. Therefore, this study aims to use crowdsourced fuzzy information enrichment through Self-healing Recommender Systems (ShRS) to provide recommendations for the best treatment therapy. It is hoped that the proper treatment therapy will cure the healing of COVID-19 patients who are self-isolating. To demonstrate the ShRS, an illustrative example was conducted. We used a crowdsourcing approach to generate treatment therapy recommendations in Bojonegoro, an area with a high number of COVID-19 cases in Indonesia. Most contextual input parameters such as age category, physical condition, and nutritional status are fuzzy. Therefore, we perform ShRS in proposing fuzzy inference to compute a new score/rank with each treatment pooled in it. The purpose of this study is to build a more practical recommendation system because the use of website applications and gadgets can open up opportunities for the public to contribute to human care. This study proposes a system to uncover the best options for healing people infected with COVID-19. It can help health practitioners and the general public cope with self-healing during a pandemic as an alternative lifesaver.
... 9,10 Based on this information, many known possible therapeutics have been tested preclinically and clinically so far, but few of them have been proven effective against this disease such as chloroquine, hydroxychloroquine, favipiravir and so on. 11 Remdisevir and chloroquine can be used effectively to cure COVID-19. 12 The Aydogdu and Hatipoglu: Electronic Structures and Reactivities of COVID-19 Drugs: ... combination of favipiravir with different antiviral agents has been studied for the treatment of COVID-19 and it has been found that the combination of antivirals is an appropriate treatment. ...
... Since molecule 1 has more hydroxyl groups, its negative regions are dominant. Thereby, it is more effective against SARS-COV-2 than that of molecule 2. 11,19,30 Molecule 3 has more red areas than the others, and they are mainly concentrated on the -NO 2 group, which removes the electron density from the molecule's π system and makes the molecule less electrophilic. The electrophilic region of molecule 4 is on the hydroxyl group while the hydrogen atoms of the amino group are the nucleophilic part. ...
These days, the world is facing the threat of pandemic Coronavirus Disease 2019 (COVID-19). Although a vaccine has been found to combat the pandemic, it is essential to find drugs for an effective treatment method against this disease as soon as possible. In this study, electronic and thermodynamic properties, molecular electrostatic potential (MEP) analysis, and frontier molecular orbitals (FMOs) of nine different covid drugs were studied with Density Functional Theory (DFT). In addition, the relationship between the electronic structures of these drugs and their biological effectiveness was examined. All parameters were computed at the B3LYP/6-311++g(d,p) level. The Solvent effect was evaluated using conductor-like polarizable continuum model (CPCM) as the solvation model. It was observed that electrophilic indexes were important to understand the efficiencies of these drugs in COVID-19 disease. Paxlovid, hydroxyquinone, and nitazoxanide were found as the most thermodynamically stable molecules. Thermodynamic parameters also demonstrated that these drugs were more stable in the aqueous media. Global descriptors and the reactivity of these drugs were found to be related. Nitazoxanide molecule exhibited the highest dipole moment. The high dipole moments of drugs can cause hydrophilic interactions that increase their effectiveness in an aqueous solution.
... We can conclude that prevention and timely treatment of the early stages of the disease can reduce its direct or indirect effects on fertility. Conventional therapies for treated COVID-19 patients include antiviral, antibiotic, steroid, and oxygen therapies (70). It is recommended to alleviate the impact of SARS-CoV-2 on fertility; testosterone levels were measured in men positive for SARS-CoV-2, and appropriate testosterone treatment is given if needed. ...
... (71). Also, anti-inflammatory drugs reduce inflammation and tissue damage in COVID-19 patients (70). There is no report on the effects of COVID-19 vaccination on fertility (72). ...
Context: The SARS-CoV-2 virus causes dysfunction of vital organs in the body. Concerns about the destructive effect of SARS-CoV-2 on human reproductive tissues and fertility have increased. Evaluation of the possible mechanisms by which SARS-CoV-2 causes infertility is essential for effective prevention and treatment. This review aims to assess the studies that have been conducted on SARS-CoV-2 impacts on the human reproductive system. Evidence Acquisition: This review study investigated articles indexed in PubMed, Science-Direct, Scopus, and google scholar databases from 2019 to 2021. The Keywords SARS-CoV-2, COVID-19, human reproductive system, testis, and ovary were searched in the mentioned databases. Results: The present study assessed the expression of SARS-CoV-2-specific receptors, the presence of the virus in the human reproductive system, and the mechanisms by which this virus can affect human fertility. Conclusions: SARS-CoV-2, like other viruses, may indirectly influence the male reproductive system through cytokine storms, inflammation-causing oxidative stress, and its possible complications. The direct effects of SARS-CoV-2 on the male reproductive system are also reported. The testis may be a potential target for the SARS-CoV-2 virus. The impact of the SARS-CoV-2 virus on women's reproductive performance is unknown and requires further investigation.
... To this end, research on concept drift, which refers to the phenomenon whereby processes change over time, is essential [130][131][132]. The evolution of the COVID-19 treatment process over time is an obvious illustration of this phenomenon [133]. Moreover, distinguishing characteristics such as the high variability of healthcare processes also make it challenging to identify and study change patterns. ...
... For instance: treatment processes are rapidly being adapted based on emerging scientific evidence [2]. A clear illustration is the COVID-19 treatment process, which rapidly changed due to the accumulation of new insights in the virus and its treatment [133,160]. PM4H should be able to cope with these circumstances. Moreover, PM4H can support the adaptation of treatment processes by, e.g., enabling the efficient comparison of processes with respect to the clinical outcomes they generate. ...
Process mining techniques can be used to analyse business processes using the data logged during their execution. These techniques are leveraged in a wide range of domains, including healthcare, where it focuses mainly on the analysis of diagnostic, treatment, and organisational processes. Despite the huge amount of data generated in hospitals by staff and machinery involved in healthcare processes, there is no evidence of a systematic uptake of process mining beyond targeted case studies in a research context. When developing and using process mining in healthcare, distinguishing characteristics of healthcare processes such as their variability and patient-centred focus require targeted attention. Against this background, the Process-Oriented Data Science in Healthcare Alliance has been established to propagate the research and application of techniques targeting the data-driven improvement of healthcare processes. This paper, an initiative of the alliance, presents the distinguishing characteristics of the healthcare domain that need to be considered to successfully use process mining, as well as open challenges that need to be addressed by the community in the future.
... therapy after long-term usage, high treatment cost, and the recurrence of disease symptoms even after months and years of treatment pose a need for the search for better therapy [19]. Natural products can serve as an unmatched treatment strategy, as far as their usage against chronic inflammatory diseases such as arthritis is concerned [11,14]. They offer a safer profile, cost-effectiveness, besides their outstanding therapeutic potential [33]. ...
... The etiology of arthritis varies with the type of arthritis and involves multiple factors that lead to T-cell and B-cells' involvement, followed by a massive flood of proinflammatory cytokines like TNF-alpha, IL-1β, and IL-6, and many more, along with gross morphological and anatomical changes like a decrease in body weight and increase in spleen size [11,42]. Proinflammatory cytokines induce synovial inflammation, and their ordered interaction plays a central role in the pathogenesis of arthritis [13]. ...
Arthritis, a primary autoimmune disorder having a global incidence of 2.03% person/year, is presently being treated by many commercially available drugs that treat symptomatically or improve the disease's clinical state; however, all the therapies pose varying amount of side effects. Therefore, it has become a fundamental need to search for therapeutics that offer better efficacy and safety profile, and the natural or nature-derived products are known for their outstanding performance in this arena. OA-DHZ, known to possess anti-inflammatory and analgesic properties, when explored for its efficacy against arthritis in adjuvant-induced arthritis (AIA) model, was found to inhibit paw edema by 34% and TNF-α, IL-6, and IL-1β by 67%, 39%, and 45% respectively when compared to diseased control. It was also able to reduce the inflamed spleen size by 45% and successfully normalized biochemical and hematological changes that followed arthritis. In vitro studies revealed that the underlying mechanism for inhibiting arthritis progression might be due to NF-κB /MAPK pathway modulation. OA-DHZ also showed selective inhibition of COX-2 in vitro while showing gastroprotective effects when evaluated for ulcerogenic and antiulcer potential in vivo. In contrast to the results obtained from in vivo experimentation, there is a disparity in the pharmacokinetic profile of OA-DHZ, where it showed low oral exposure and high clearance rate. OA-DHZ being antiarthritic acting via NF-κB /MAPK/ COX inhibition while showing gastro-protective effects, can be a suitable candidate to be in the drug pipeline and further exploration.
... The present therapeutic strategies to combat SARS-CoV-2 infection are nonspecific, symptomatic, and supportive. The current therapies used to control the pathophysiology of COVID-19 patients include antiviral drugs, antibiotics, glucocorticoids, and mechanical ventilation [10][11][12]. However, there is no specific therapy approved for the treatment of COVID-19 so far. ...
... The understanding of the COVID-19 pathophysiology so far suggests that an antiviral therapy alone may not be able to control the severity and high mortality rate in advanced stages of the disease [11]. It has been well-documented that there is an exaggerated immune response leading to cytokine storm in COVID-19 patients [25]. ...
Background:
The coronavirus disease-19 (COVID-19) pandemic is a serious devastating disease and has posed a global health emergency. So far, there is not any specific therapy approved till date to control the clinical symptoms of the disease. Remdesivir has been approved by the FDA as an emergency clinical therapy. But it may not be effective alone to control the disease as it can only control the viral replication in the host.
Summary:
This article summarizes the possible therapeutic potential and benefits of using montelukast, a cysteinyl leukotriene 1 (CysLT1) receptor antagonist, to control COVID-19 pathophysiology. Montelukast has shown anti-inflammatory effects, reduced cytokine production, improvement in post-infection cough production and other lung complications. Key Messages: Recent reports clearly indicate a distinct role of CysLT-regulated cytokines and immunological signaling in COVID-19. Thus, montelukast may have a clinical potential to control lung pathology during COVID-19.
... Wild animals sold in the market may be a source of infection. Genomic sequencing of a virus from Rhinolophus affinis bat (bat-RaTG13) showed 96% identity with the genomic sequence of SARS-CoV-2 (Chibber et al. 2020). Similarly, genome sequencing of a pangolin coronavirus obtained from illegally imported Malayan pangolins in Guangdong province, China, had a sequence identical to that of SARS-CoV-2. ...
... Al-Bari (2015), Chibber et al. (2020), and Liu et al. (2020b) demonstrated that the molecular mechanisms of action of chloroquine and hydroxychloroquine drugs are similar, but they interfere with virus replication in distinct ways. They inhibit binding of the S proteins to host cell ACE2 receptors by blocking terminal glycosylation (Kalra et al. 2020). ...
Diseases negatively impact the environment, causing many health risks and the spread of pollution and hazards. A novel coronavirus, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has led to a recent respiratory syndrome epidemic in humans. In December 2019, the sudden emergence of this new coronavirus and the subsequent severe disease it causes created a serious global health threat and hazards. This is in contrast to the two aforementioned coronaviruses, SARS-CoV-2 (in 2002) and middle east respiratory syndrome coronavirus MERS-CoV (in 2012), which were much more easily contained. The World Health Organization (WHO) dubbed this contagious respiratory disease an “epidemic outbreak” in March 2020. More than 80 companies and research institutions worldwide are working together, in cooperation with many governmental agencies, to develop an effective vaccine. To date, six authorized vaccines have been registered. Up till now, no approved drugs and drug scientists are racing from development to clinical trials to find new drugs for COVID-19. Wild animals, such as snakes, bats, and pangolins are the main sources of coronaviruses, as determined by the sequence homology between MERS-CoV and viruses in these animals. Human infection is caused by inhalation of respiratory droplets. To date, the only available treatment protocol for COVID-19 is based on the prevalent clinical signs. This review aims to summarize the current information regarding the origin, evolution, genomic organization, epidemiology, and molecular and cellular characteristics of SARS-CoV-2 as well as the diagnostic and treatment approaches for COVID-19 and its impact on global health, environment, and economy.
... Immune-based therapies for COVID-19 are considered as systemic treatments, using human blood-derived products and/or immune-modulatory therapies. As of blood-derived products, those who have recovered from SARS-CoV-2 infection can donate their convalescent plasma or immunoglobulin to make products for treatment in other patients [52,53]. Experimental data suggested that, these products induce direct inhibitory effect against SARS-CoV-2 [53]. ...
... As of blood-derived products, those who have recovered from SARS-CoV-2 infection can donate their convalescent plasma or immunoglobulin to make products for treatment in other patients [52,53]. Experimental data suggested that, these products induce direct inhibitory effect against SARS-CoV-2 [53]. There is not enough evidence in clinical data for blood-derived products to be recommended by the guidelines as a standard care treatment for COVID-19 [2,3,5]. ...
... Additionally, the experimental application of other medications like ivermectin, azithromycin combined with hydroxychloroquine, and newer antiviral agents such as favipiravir. Also, ongoing clinical trials and the worldwide scientific endeavor to devise innovative drugs that address specific facets of the virus's life cycle and mechanisms of infection" [22,23]. ...
In this review research, the full bio-medical potential and application of the severe acute respiratory syndrome (SARS)-CoV-2 viruses are discussed in detail with the aim of discovering innovative treatment strategies in virology and medicine. The SARS-CoV-2 which caused an international health crisis also unraveled an opportunity to gain from its pathogenic effects to treat the affected people. The study aims at testing whether the newly discovered SARS-CoV-2 can be used for therapeutic and clinical purposes. With in-depth analytics, this investigation issue endeavors to unearth new ways of fighting infectious diseases and to improve existing medical interventions. Beside scientific and practical significance the role of this work is vital. By learning the biologic and molecular mysteries of SARS-CoV-2, the researchers can create precise medicines and vaccines not only against COVID-19 but also the other infectious diseases as well. Furthermore, this recommendation may open the door to the future development of gene therapy and vaccine technology. In this sense, it combines multiple approaches, such as viral studies, immunology, and molecular biology. Laboratory experiments, computer program modeling and clinical trials are applied to detection of the SARS-COV-2 in therapeutic implementation. The principal conclusion and analysis of this research put forth the fact that SARS-CoV-2 can be utilized in anti-viral treatment, cancer therapy, and vaccine programs. The study results confirm the inherent adaptability of viruses like SARS-CoV-2 and emphasis on the development of specific therapeutic measures. It is valuable because of its potential to add to virology and medication, showing new ways for virus-based treatment. In addition, the impact of these results on treatments would be revolutionary, with potential to invent superior and flexible interventions against infectious disease. In short, the therapeutic use of SARS-CoV-2 can be regarded as a bold innovation with tremendous consequences for general health, and ultimately for medical science.
... Before administering live-attenuated virus vaccines in the community, older individuals should be immunized with non-proliferative vaccines to develop mucosal immunity against SARS-CoV-2. Three live-attenuated virus vaccines, favipiravir, remdesivir, and ribavirin, have been approved and are widely used worldwide [306]. Live-attenuated viral vaccines hinder SARS-CoV-2 from causing persistent effects on human organ systems; therefore, Chen et al. [36] prepared a live-attenuated viral vaccine (dNS1-RBD), applied intranasally on the animal model (mice), for prolonged investigation (one year) on pathological effects caused by SARS-CoV-2 on the respiratory system. ...
SARS-CoV-2, the highly contagious pathogen responsible for the COVID-19 pandemic, has persistent effects that begin four weeks after initial infection and last for an undetermined duration. These chronic effects are more harmful than acute ones. This review explores the long-term impact of the virus on various human organs, including the pulmonary, cardiovascular, neurological, reproductive, gastrointestinal, musculoskeletal, endocrine, and lymphoid systems, particularly in older adults. Regarding diagnosis, RT-PCR is the gold standard for detecting COVID-19, though it requires specialized equipment, skilled personnel, and considerable time to produce results. To address these limitations, artificial intelligence in imaging and microfluidics technologies offers promising alternatives for diagnosing COVID-19 efficiently. Pharmacological and non-pharmacological strategies are effective in mitigating the persistent impacts of COVID-19. These strategies enhance immunity in post-COVID-19 patients by reducing cytokine release syndrome, improving T cell response, and increasing the circulation of activated natural killer and CD8 T cells in blood and tissues. This, in turn, alleviates symptoms such as fever, nausea, fatigue, muscle weakness, and pain. Vaccines, including inactivated viral, live attenuated viral, protein subunit, viral vectored, mRNA, DNA, and nanoparticle vaccines, significantly reduce the adverse long-term effects of the virus. However, no vaccine has been reported to provide lifetime protection against COVID-19. Consequently, protective measures such as physical distancing, mask usage, and hand hygiene remain essential strategies. This review offers a comprehensive understanding of the persistent effects of COVID-19 on individuals of varying ages, along with insights into diagnosis, treatment, vaccination, and future preventative measures against the spread of SARS-CoV-2.
... However, no effect of the drug was seen in patients with mild conditions who did not require supportive oxygen therapy. The WHO has also authorized the use of dexamethasone only in critical situations (14). ...
The new coronavirus was first identified in China in December 2019 and then, it created a widespread pandemic around the world. There is currently no definitive cure for it and it will not be possible to make a vaccine soon. Pathogenic mechanism of the virus includes virus entry, binding to angiotensin-converting enzyme 2 (ACE2) receptors on the surface of host cells, proliferation, membrane fusion, assembly, subsequent infection, cytokine secretion, and the host immune response to the virus. By identifying at what stage the patient is, possible effective drugs can be used to control each stage. Therefore, identifying the mechanism of action of the virus in different stages of the disease makes it possible to use the appropriate drug for each stage of the disease and control the disease.
... Since COVID-19 became an epidemic, the effects of various antiviral drugs on patients with COVID-19 have been studied [16]. At present, patients with positive COVID-19 are receiving antiviral, antibiotic and steroid therapies [17]. The effect of these drugs on the final outcome of COVID-19 treatment is not yet clear, and it is possible that these drugs treat the patient and reduce the recovery time. ...
Objectives
Different drugs have different effects on the prognosis of patients with COVID-19. This study aimed to evaluate the effect of different drug regimens on patients with COVID-19, hospitalized in Sanandaj city.
Methods
In this retrospective cohort study, 660 patients with COVID-19, hospitalized in the Tohid, Kowsar and Besat hospitals located Sanandaj (Kurdistan Province, Iran) were studied from February 2020 to February 2021 with clinical symptoms and positive test results.
Results
The results of multivariate regression analysis showed the days of hospitalization for patients who had received the drug regimen 2 (Interferons (ReciGen/Ziphron) or Interferon Vectra (lopinavir/ritonavir)) was 1.92 times higher than those who had received the drug regimen 1 (hydroxychloroquine group or a combination of chloroquine and azithromycin) while a significant association was observed (OR = 1.92, 95% CI: 1.16–3.16, P = 0.011). Also, the hospitalization in ICU was longer in patients treated by the drug regimen 2 (Interferons (ReciGen/Ziphron) or Interferon Vectra (lopinavir/ritonavir)) (OR = 4.63, 95% CI: 1.80–11.82, P = 0.001), however, drug regimens did not show a significant effect on mortality and use of ventilator in patients ( P > 0.05).
Conclusion
The study results showed the drug regimens 2 and 5 increased the days of hospitalization and hospitalization in ICU, respectively, while the other drug regimens had no significant effect on mortality and use a ventilator in the studied patients and none of the drug regimens had an effect on reducing mortality compared to other ones.
... For patients with autoimmune disorders, certain drug molecules, such as hydroxychloroquine, did not show the required concentration of drug in the plasma, leading to hindrance in inhibiting SARS-CoV-2 [50,55,56]. Handling patients with COVID-19 already suffering from autoimmune disorders is mentioned in the treatment guidelines of the National Institutes of Health and the American College of Rheumatology guidelines for the management of adult patients with the rheumatic disease [57]. As different variants of the virus have been found, specialized therapy and therapeutic management have become available. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a major health concern worldwide and evolved into different variants. SARS-CoV-2 possesses a spike glycoprotein on its envelope that binds to the angiotensin-converting enzyme 2 (ACE-2) receptor of the host cell via the receptor-binding domain (RBD) in the upper respiratory tract. Since the SARS-CoV-2 virus variants changes the seveirity of dieseases and treatment scenarios, repurposing current medicines may provide a quick and appealing method with established safety features. The efficacy and safety of antiviral medicines against the coronavirus disease 2019 (COVID-19) have been investigated, and several of them are now undergoing clinical studies. Recently, it has been found that nitric oxide (NO) shows antiviral properties against SARS-CoV-2 and prevents the virus from binding to a host cell. In addition, NO is a well-known vasodilator and acts as an important coagulation mediator. With the fast-track development of COVID-19 treatments and vaccines, one avenue of research aimed at improving therapeutics is exploring different forms of drug delivery, including intranasal sprays and inhalation therapy. The nasal mucosa is more prone to be the site of infection as it is in more direct contact with the physical environment via air during inhalation and exhalation. Thus, the use of the exogenous nasal NO therapy via the intranasal route displays a distinct advantage. Therefore, the objective of this review is to summarize the relevant actions of NO via intranasal spray and inhalation delivery, its mechanism of action, and its use in the treatment of COVID-19.
... Coronavirus disease 2019 is a challenging disease. To date, many treatment options have been used, either based on emergency approval or evidence-based medicine [13,14]. This pharmacological therapy ranges between COVID-19-specific medications and COVID-19-nonspecific medications [15]. ...
There are many treatment modalities for COVID-19 – with varied outcome. Therefore, authors designed this study to assess prescribing patterns and the clinical outcome for hospitalized patients with severe and critical COVID-19 so as to determine the most effective approach.
Authors conducted a retrospective observational study on 346 adult patients with either severe or critical COVID-19, who were admitted to public hospitals in Al-Najaf city, Iraq from June to September 2020. Patients’ information, medications and outcomes were collected from their medical records in the registered office of the hospital.
A total of 346 patients were enrolled, with a majority of patients being adults above 35 years old and male (70.2%). Most patients (81%) received corticosteroid as dexamethasone, and about 45% of all patients were given convalescent plasma therapy, while a few patients were prescribed antiviral favipiravir (23%) and lopinavir/ritonavir (19%). As supportive care medications, anticoagulant such as enoxaparin was administered to most of the patients (93%) and more than half of all patients received the broad-spectrum antibiotic, meropenem.
The majority of the patients recovered and were discharged alive (66%), however, the in- hospital mortality rate was 26%. Interestingly, patients treated with enoxaparin alone or in combination with hydroxychloroquine were associated with better outcome.
The prescribing pattern of COVID-19 specific medications and supportive care is aligned with guideline recommendations and associated with a beneficial therapeutic outcome.
... In case of variant omicron (BA.1, its subvariant, BA.2, and BA. 3), it carries about 30 mutations in the gene for the S-protein. 121 Since the majority of COVID-19 vaccines and human made therapeutic antibodies targeted S protein of the virus, 121,124 these mutations not only make the virus more infectious or transmissible but also enable the virus to overcome a host's immune response, 120 vaccination-enhanced immunity, and antibody therapies. ...
Since the beginning of the SARS-CoV-2 pandemic, the treatments and management of the deadly COVID-19 disease have made great progress. The strategies for developing novel treatments against COVID-19 include antiviral small molecule drugs, cell and gene therapies, immunomodulators, neutralizing antibodies, and combination therapies. Among them, immunomodulators are the most studied treatments. The small molecule antiviral drugs and immunoregulators are expected to be effective against viral variants of SARS-CoV-2 as these drugs target either conservative parts of the virus or common pathways of inflammation. Although the immunoregulators have shown benefits in reducing mortality of cytokine release syndrome (CRS) triggered by SARS-CoV-2 infections, extensive investigations on this class of treatment to launch novel therapies that substantially improve efficacy and reduce side effects are still warranted. Moreover, great challenges have emerged as the SARS-CoV-2 virus quickly, frequently, and continuously evolved. This review provides an update and summarizes the recent advances in the treatment of COVID-19 and in particular emphasized the strategies in managing CRS triggered by SARS-CoV-2. A brief perspective in the battle against the deadly disease was also provided.
... These are already approved by the USFDA (fast track approval) and the UK regulators and ethical reviewers along with regulatory authority of Brazil (Anvisa), respectively. In India, Zydus Cadila has obtained the approval for its vaccine candidate, namely, "ZyCoV-D" from Drugs Controller General of India (DCGI) to initiate phase 1/2 clinical trials [CTRI/2020/07/026352] (10,11). After getting positive result in preclinical study on mice, rats, guinea pigs, and rabbits, ZyCoV-D is moving towards phase 1/2 study. ...
COVID-19 caused by coronavirus SARS-CoV-2 became a serious threat to humankind for the past couple of years. The development of vaccine and its immediate application might be the only to escape from the grasp of this demoniac pandemic. Approximately 343 clinical trials on COVID-19 vaccines are ongoing currently, and almost all countries are motivating ongoing researches at warp speed for the development of vaccines against COVID-19. This review explores the progress in the development of the vaccines, their current status of ongoing clinical research, mechanisms, and regulatory approvals. Many pharmaceutical companies are already in the endgame for manufacturing various vaccines of which some are already being marketed across the globe, while others are yet to get approval for marketing. The primary aim of this review is to compare regulatory accepted vaccines in terms of their composition, doses, regulatory status, and efficacy. The study is conducted by grouping into approved and unapproved vaccines for marketing. Different routes of administration of vaccines along with the efficacy of the routes are also presented in the review. A wide range of database and clinical trial data is reviewed for sorting out the information on different vaccines. Unfortunately, many mutations (alpha, beta, gamma, delta, kappa, omicron etc.) of SARS-CoV-2 have attacked people in very short time, which is the great challenge for investigational vaccines. Moreover, some vaccines like Pfizer's BNT162, Oxford's ChAdOx1, Moderna's mRNA-1273, and Bharat Biotech's Covaxin have got regulatory approval in some countries for its distribution which may prove to stand tall against the pandemic.
... However, systematic reviews and meta-analyses are at the top of the clinical evidence hierarchy and can decide whether nutraceutical agents should be used in the clinical setting. Fortunately, there were recent advances in the management of COVID-19, including antiviral agents, monoclonal antibodies along with supportive care measures, oxygen therapy, and usage of corticosteroids (28)(29)(30). The purpose of this systematic review is to highlight the multi-therapeutic effects of curcumin as a dietary supplement in reducing inflammation, relieving the symptoms of COVID-19, and accelerating the recovery process. ...
Accumulating evidence has been reported regarding the effect of curcumin as a dietary antiviral on patients with COVID-19; however, findings are controversial. Our systematic review aimed to evaluate the effects of curcumin in patients with COVID-19. Electronic databases (PubMed, EMBASE, Scopus, Web of Science, Cochrane Central, and Google Scholar) were systematically searched to identify only randomized clinical trials (RCTs) that assessed curcumin in patients with COVID-19 from inception to September 23, 2021 relevant keywords. The Cochrane risk-of-bias tool for randomized trials was used to evaluate the risk of bias. After a critical review of 1,098 search hits, only six RCTs were selected for discussion. A total of 480 patients were included, with 240 amongst the curcumin groups and 240 in the control group. The lymphocyte count was significantly higher in the curcumin group compared to the placebo group. Curcumin was found to decrease the number of T-helper 17 cells, downregulate T-helper-17 cell-related factors, reduce levels of T-helper-17 cell-related cytokines, yet increase the gene expression of Treg transcription factor forkhead box P3 (FOXP3), and decrease T-Box transcription factor 21 (TBX21). Our review revealed that curcumin might have a positive effect on relieving COVID-19 related inflammatory response due to its powerful immune-modulatory effects on cytokines production, T-cell responses, and gene expression. These findings suggest that curcumin confers clinical benefits in patients with COVID-19. However, due to the limited number of the included studies, further high-quality studies are needed to establish the clinical efficacy of the curcumin.
... ,33 The therapeutic strategies are likely to vary between countries. For instance, in the United States, studies of pregnant women early in the pandemic indicated frequent exposure (usually after the first trimester) to hydroxychloroquine, Remdesivir and azithromycin.2,14 ...
Background:
The COVID-19 pandemic has accelerated pregnancy outcome research, but little attention has been given specifically to the risk of congenital anomalies (CA) and first trimester exposures.
Objectives:
We reviewed the main data sources and study designs used internationally, particularly in Europe, for CA research, and their strengths and limitations for investigating COVID-19 disease, medications and vaccines.
Population:
We classify research designs based on four data sources: a) spontaneous adverse event reporting, where study subjects are positive for both exposure and outcome, b) pregnancy exposure registries, where study subjects are positive for exposure, c) congenital anomaly registries, where study subjects are positive for outcome and d) population healthcare data where the entire population of births is included, irrespective of exposure and outcome.
Study design:
Each data source allows different study designs, including case series, exposed pregnancy cohorts (with external comparator), ecological studies, case-control studies and population cohort studies (with internal comparator).
Methods:
The quality of data sources for CA studies is reviewed in relation to criteria including diagnostic accuracy of CA data, size of study population, inclusion of terminations of pregnancy for foetal anomaly, inclusion of first trimester COVID-19-related exposures and use of an internal comparator group. Multinational collaboration models are reviewed.
Results:
Pregnancy exposure registries have been the main design for COVID-19 pregnancy studies, but lack detail regarding first trimester exposures relevant to CA, or a suitable comparator group. CA registries present opportunities for improving diagnostic accuracy in COVID-19 research, especially when linked to other data sources. Availability of inpatient hospital medication use in population healthcare data is limited. More use of ongoing mother-baby linkage systems would improve research efficiency. Multinational collaboration delivers statistical power.
Conclusions:
Challenges and opportunities exist to improve research on CA in relation to the COVID-19 pandemic and future pandemics.
... Thus, repurposing developed drugs for the treatment of multiple diseases has become a common approach, since it utilizes de-risked substances along with wellknown pre-clinical, pharmacokinetic and pharmacodynamic profiles that would be fast tracked through to phase 3 human clinical trials, making the drug discovery procedure comparatively inexpensive and quick. As a result, the WHO as well as other health organizations have reconsidered the effectiveness of approved and potential medications to treat existing health problems (Supplementary Table 2 [75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93]) [67]. On the downside, however, due to the 'burden' of intellectual property and the related expenditures, many pharmaceutical companies are cautious about fully exploiting the possibilities of drug repurposing. ...
The COVID-19 pandemic is a lethal virus outbreak by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has severely affected human lives and the global economy. The most vital part of the research and development of therapeutic agents is to design drug products to manage COVID-19 efficiently. Numerous attempts have been in place to determine the optimal drug dose and combination of drugs to treat the disease on a global scale. This article documents the information available on SARS-CoV-2 and its life cycle, which will aid in the development of the potential treatment options. A consolidated summary of several natural and repurposed drugs to manage COVID-19 is depicted with summary of current vaccine development. People with high age, comorbity and concomitant illnesses such as overweight, metabolic disorders, pulmonary disease, coronary heart disease, renal failure, fatty liver and neoplastic disorders are more prone to create serious COVID-19 and its consequences. This article also presents an overview of post-COVID-19 complications in patients.
... In the absence of a virus, phosphorylation activates STAT1 and can interact with IFN regulatory factor 9, which produces the IFN-stimulated gene factor 3 transcription complexes. This complex gets into the nucleus and binds to the IFN-stimulated response element, promoting host's anti-viral response [23][24][25][26][27]. Ivermectin has the potential to target and inhibit SARS-CoV-2 replication by blocking viral entry into the nucleus. ...
The global COVID-19 pandemic has affected the world's population by causing changes in behavior, such as social distancing, masking, restricting people's movement, and evaluating existing medication as potential therapies. Many pre-existing medications such as tocilizumab, ivermectin, colchicine, interferon, and steroids have been evaluated for being repurposed to use for the treatment of COVID-19. None of these agents have been effective except for ster-oids and, to a lesser degree, tocilizumab. Ivermectin has been one of the suggested repurposed medications which exhibit an in vitro inhibitory activity on SARS-CoV-2 replication. The most recommended dose of ivermectin for the treatment of COVID-19 is 150-200 µg/kg twice daily. As ivermectin adoption for COVID-19 increased, the Food and Drug Administration (FDA) issued a warning on its use during the pandemic. However, the drug remains of interest to clinicians and has shown some promise in observational studies. This narrative reviews the toxicological profile and some potential therapeutic effects of ivermectin. Based on the current dose recommendation, ivermectin appears to be safe with minimum side effects. However, serious questions remain about the effectiveness of this drug in the treatment of patients with COVID-19.
... Several approaches have been undertaken to further understand the SARS-CoV-2 infection pattern and to find possible treatment options; for example, it has been speculated that numerous antiviral drugs, such as oseltamivir, lopinavir, interferon-alpha (IFN-α), remdesivir, among others, could be plausible options to treat COVID-19 patients. Nevertheless, there is no conclusive clinical evidence about the effectiveness and safety of the abovementioned drugs (Chibber et al., 2020). Under this premise, using the principles and molecular participants of gene regulation mechanisms might represent an innovative way to inhibit and ameliorate COVID-19 infection. ...
Nowadays, one of the major global health concerns is coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Even though numerous treatments and vaccines to combat this virus are currently under development, the detailed molecular mechanisms underlying the pathogenesis of this disease are yet to be elucidated to design future therapeutic tools against SARS-CoV-2 variants. MicroRNAs (miRNAs) are small (20-24 nucleotides), non-coding RNA molecules that regulate post-transcriptional gene expression. Recently, it has been demonstrated that both host and viral-encoded miRNAs are crucial for the successful infection of SARS-CoV-2. For instance, dysregulation of miRNAs that modulate multiple genes expressed in COVID-19 patients with comorbidities (e.g., type 2 diabetes, lung adenocarcinoma, and cerebrovascular disorders) could affect the severity of the disease. Thus, altered expression levels of circulating miRNAs might be helpful to diagnose this illness and forecast whether a COVID-19 patient could develop a severe state of the disease. Besides, researchers have found a number of miRNAs could inhibit the expression of proteins such as ACE2, TMPRSS2, spike, and Nsp12, involved in the life cycle of SARS-CoV-2. Accordingly, miRNAs represent potential biomarkers and therapeutic targets for this devastating viral disease. Therefore, in this current review, we present the recent discoveries regarding the clinical relevance and biological roles of miRNAs in COVID-19.
... SARS-CoV-2 is a single-stranded, positive-stranded RNA virus between 60 and 140 nm in diameter with corona-like projections on its surface, formed by the spike glycoproteins (protein S), crucial for invading target cells [8]. Immune response is a key part of the clinical evolution of the disease, in which cytokine storm, leucopenia, and lung infiltrating macrophages and neutrophils are associated with poorer outcomes [2,9,10]. ...
The cellular immune response plays an important role in COVID-19, caused by SARS-CoV-2. This feature makes use of in vitro models’ useful tools to evaluate vaccines and biopharmaceutical effects. Here, we developed a two-step model to evaluate the cellular immune response after SARS-CoV-2 infection-induced or spike protein stimulation in peripheral blood mononuclear cells (PBMC) from both unexposed and COVID-19 (primo-infected) individuals (Step1). Moreover, the supernatants of these cultures were used to evaluate its effects on lung cell lines (A549) (Step2). When PBMC from the unexposed were infected by SARS-CoV-2, cytotoxic natural killer and nonclassical monocytes expressing inflammatory cytokines genes were raised. The supernatant of these cells can induce apoptosis of A549 cells (mock vs. Step2 [mean]: 6.4% × 17.7%). Meanwhile, PBMCs from primo-infected presented their memory CD4⁺ T cells activated with a high production of IFNG and antiviral genes. Supernatant from past COVID-19 subjects contributed to reduce apoptosis (mock vs. Step2 [ratio]: 7.2 × 1.4) and to elevate the antiviral activity (iNOS) of A549 cells (mock vs. Step2 [mean]: 31.5% × 55.7%). Our findings showed features of immune primary cells and lung cell lines response after SARS-CoV-2 or spike protein stimulation that can be used as an in vitro model to study the immunity effects after SARS-CoV-2 antigen exposure.
... In general, for mild to severe cases of infection, antiviral drugs, antibiotics, steroids, antiinflammatory drugs, low-molecular-weight heparin, biological agents such as hyperimmune immunoglobulins, and convalescent plasma are used [103]. According to guidelines issued by the National Health Commission and State, the administration of several drugs has been recommended for COVID-19 treatment, including lopinavir, ritonavir, arbidol, chloroquine phosphate, ribavirin, remdesivir, tocilizumab, etc. Chloroquine phosphate, a potential antiviral drug, helps to inhibit pneumonia exacerbation and reduce disease course during COVID-19 infection [104], although hydroxychloroquine has been proven to be better in fighting the infection than chloroquine in the context of dose-dependent toxicity profile [105]. Azithromycin, along with hydroxychloroquine, is reported to be useful for virus removal in COVID-19 infection [105]. ...
Concurrent waves of coronavirus disease, Ebola virus disease, avian influenza A, and black fungus are jeopardizing lives in some parts of Africa and Asia. From this point of view, this review aims to summarize both the socio-economic and public health implications of these parallel outbreaks along with their best possible management approaches. Online databases (PubMed/PMC/Medline, Publons, ResearchGate, Scopus, Google Scholar, etc.) were used to collect the necessary information regarding these outbreaks. Based on the reports published and analyses performed so far, the long-lasting impacts caused by these simultaneous outbreaks on global socio-economical and public health status can be conceived from the past experiences of outbreaks, especially the COVID-19 pandemic. Moreover, prolonged restrictions by the local government may lead to food insecurity, global recession, and an enormous impact on the mental health of people of all ages, specifically in developing countries. Such overwhelming effects have already been reported to be declining the national growth of the economy as well as increasing political insecurity and shortage of basic needs. Although various actions have already been taken, including vaccination, clinical management and further research, social distancing, lockdown, etc., to improve the situation, the emerging variants and associated genetic mutations may make containment difficult, worsening the situation again. So, considering the current mutational dynamics of the pathogens and past experiences, perpetual preparedness along with updated clinical management backed by epidemiological studies and innovative scientific effort are inevitable to combat the simultaneous waves of multiple infectious diseases.
... A lot of simple indole derivatives was reported as antimicrobial and antifungal agents in several studies as compounds I [4] and II [5] ( Fig. 1 ). Also, the use of indole scaffold is widespread in antiviral research such as Delavirdine III [6] and Arbidol IV [7] . While a number of indole-derivatives go through clinical stages, such as Fosdevirine V and Atevirdine VI [6] ( Fig. 1 ). ...
In short reaction time with excellent yield, we designed and synthesized a series of indole linked azole ring at position-2 as thiazole and pyrazole moieties under microwaves irradiation. The structures and mechanistic pathways were discussed in this context using all available spectroscopic techniques. On the other hand, in some cases, the spectral data failed to differentiate and confirm the actual structure of some reactions, thus, we used the functional density theory calculations performed at the B3LYP / 6-31G (d, p) level of the theory in order to distinguish the most stable derivative. The antimicrobial activity of selected derivatives showed moderate to good activity against some strains of bacteria and fungi while, indole-linked-pyrazole derivative 20 showed superior antifungal activity against Aspergillus fumigatus. Moreover, the pharmacokinetic and pharmacodynamic profiles were calculated and studied for all synthesized indole derivatives. Using the Molecular docking to study the affinities of the new derivatives to binding site of three SARS-CoV-2 enzymes (polymerase, helicase, and methyltransferase) to investigate their antiviral activity against SARS-CoV-2. The results indicated that all compounds have excellent energy level; docking scores from -6.5 to – 8.7 Kcal/mol in comparison with ligand score -5.5 Kcal/mol.
... Ifn-γ Hemophagocytic lympho-histiocytosis (HlH) 175 approved by fDa in 2018. It is currently under investigation for its efficacy against cytokine storm in CovID 19. ...
As a natural function, antibodies defend the host from infected cells and pathogens by recognizing their pathogenic determinants. Antibodies (Abs) gained wide acceptance with an enormous impact on human health and have predominantly captured the arena of bio-therapeutics and bio-diagnostics. The scope of Ab-based biologics is vast, and it is likely to solve many unmet clinical needs in future. The majority of attention is now devoted to developing innovative technologies for manufacturing and engineering Abs, better suited to satisfy human needs.
... Although new treatments and COVID-19 vaccines are being developed and approved via Emergency Use Authorization (EUA) worldwide to mitigate the impact of the pandemic (7). Nevertheless, the population informed choices regarding preventive measures are still essential as the time scale for vaccine coverage world wide and the continuous emergence of new varients of concern influences the timeline of pandemic end (8). ...
Population's preventive practices and self-isolation is determinantal in the prevention and mitigation. This study explored the adult population's knowledge, attitude, and practice toward COVID-19 in UAE between the 4th and 14th of April 2020. The study was a community-based, cross-sectional study using a self-administered electronic questionnaire covering five different aspects: demographics, knowledge, practice, attitude, source, and trust of information, and a patient health questionnaire (PHQ-2) for depression screening. Results were analyzed using frequencies, cross-tabulation, and regression analysis. A total of 1,867 people responded to the survey. The mean age of participants was 36.0 years S.D. 10.8. Males were 19.3% and female (80.7%). Knowledge was significantly better in people with higher educational levels (B 0.17, P-value < 0.001), good preventive practice (B 0.12, P-value < 0.001), and higher perceived risk scores (B 0.053, P-value = 0.025). The best practice scores were shown by participants with older age (B 0.097, P-value < 0.05), with good knowledge (B 0.086, P-value < 0.05), were of non-UAE nationalities (B −0.08, P-value < 0.05), with jobs that cannot be practiced from home, military and health care employees (B −0.104, P-value < 0.05), had a personal history of contact with COVID-19 patients (B 0.053, P-value < 0.05), higher educational levels (B 0.052, P-value < 0.05), and a positive attitude toward taking a vaccine (B 0.088, P-value < 0.05). Depression risk was significantly higher in men, non-UAE nationals, in those with lower knowledge scores, and younger ages. The most followed practices were staying home, handwashing, avoiding social gatherings, limiting three people per vehicle, and avoiding public transportation. The least practiced measures were covering the face while sneezing or coughing and wearing masks. Although staying home was reported by 92.5% of participants, 22.6% mentioned that they were visited by more than two people and visited others in 18.4% during the last week. Social media was the source of information for 82.1% of the participants and most trusted doctors and healthcare providers. Depression risk was present in 18.9% of the participants, and most respondents (89%) agreed that SARS-COV-2 infection would be finally be successfully controlled. An encouraging finding is the willingness of two-third of the participants (64.5%) to take the COVID-19 vaccine and if it was developed, although it was very early in the pandemic. Only 14.6% said they would not take the vaccine, and 20.9% were not sure. The obtained results on knowledge and practices, although satisfactory, could be insufficient to prevent this pandemic from being contained. Therefore, we recommend the intensification of awareness programs and good practices. In addition, mental health is an area worth further studies.
... [90,91] Emapalumab (Gamifant) can bind and inactivate interferon gamma. [92][93][94] Gimsilumab acts by targeting granulocyte macrophage-colony stimulating factor is a growth factor. [95][96][97] REGN-COV2 binds noncompetitively to spike protein of SARS-CoV-2 on receptor binding domain. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a virus with single positive-strand RNA, having glycoproteins projection on envelopes so reveals a halo-like appearance or corona. Coronavirus is of four types: (1) α-coronavirus (α-COV); (2) β-coronavirus (β-COV); (3) δ-coronavirus (δ-COV); and (4) γ-coronavirus (γ-COV) and belongs to family Coronaviridae and subfamily Coronavirinae. Coronaviruses are the normal pathogens that cause broad band of gastrointestinal and respiratory diseases in domestic as well as wild animals such as pigs, birds, and rodents. Coronavirus is highly infectious in case of elders for mortality rate. The elder peoples are at 2-fold higher risk as compared to the younger population and the greater part of the population dying from coronavirus disease (COVID-19) is male. The virus enters into the body by the mouth, eyes, or nose, then particles march inside of the body by different pathways and affect vital organs in severe ways such as liver, heart muscle, blood vessels, kidneys, central nervous system, etc. Right now, the only solution to avoid COVID-19 infection is “precautions.” Different companies of different countries at different steps are in race to develop effective medicines for treatment and management of the same. Here, in this review, we tried to give an overview of all about SARS-CoV-2, COVID-19 infection, pathophysiology, mechanisms, and various treatment trials.
... cin) as alone or in combination are at different stages of investigation in multiple clinical trials globally for prophylactic as well as treatment of this disease (Chibber, Haq, Ahmed, Andrabi, & Singh, 2020;Horby et al., 2020;Luo et al., 2020;Million et al., 2020;Rabby, 2020;M. A. Rahman et al., 2020;Scavone et al., 2020). ...
Emergence of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection, COVID‐19, has become the global panic since December 2019, which urges the global healthcare professionals to identify novel therapeutics to counteract this pandemic. So far, there is no approved treatment available to control this public health issue; however, a few antiviral agents and repurposed drugs support the patients under medical supervision by compromising their adverse effects, especially in emergency conditions. Only a few vaccines have been approved to date. In this context, several plant natural products‐based research studies are evidenced to play a crucial role in immunomodulation that can prevent the chances of infection as well as combat the cytokine release storm (CRS) generated during COVID‐19 infection. In this present review, we have focused on flavonoids, especially epicatechin, epigallocatechin gallate, hesperidin, naringenin, quercetin, rutin, luteolin, baicalin, diosmin, ge nistein, biochanin A, and silymarin, which can counteract the virus‐mediated elevated levels of inflammatory cytokines leading to multiple organ failure. In addition, a comprehensive discussion on available in silico, in vitro, and in vivo findings with critical analysis has also been evaluated, which might pave the way for further development of phytotherapeutics to identify the potential lead candidatetoward effective and safe management of the SARS‐CoV‐2 disease.
... For hepatitis, interferon-alpha (IFN-α) is extensively utilized, it's a wide scope anti-viral drug. IFN-α is reported to decrease the replication of SARS-CoV-2 in the in vitro conditions [109]. Interferon-beta (IFN-β) is a naturally existing protein molecule that puts together the anti-viral bodily responses [70]. ...
Respiratory diseases are the leading source of morbidity and death for millions around the world of all ages. A 2019 coronavirus outbreak has occurred in China and is spread quickly throughout nearly all across the world. To introduce prevention measures that have contributed to a sudden upturn in the rate of cases around the globe, several nations responded too late. It has prompted nations to close the borders, halted companies, kept people inside their homes, and numerous other measures to prevent their spread. We systematically searched on Google scholar, PubMed, LitCovid, and MedRxiv using the search terms coronavirus, severe acute respiratory syndrome, 2019-nCoV, SARS-CoV-2, SARS-CoV, MERS-CoV, COVID-19, and vaccine for published articles. Present or performed clinical studies were found on the ClinicalTrials. gov, the Chinese Clinical Trial Registry, and the International Clinical Trial Registry site using the disease searches phrase coronavirus infection. Many repurposed drugs, including antivirals, antibiotics, monoclonal antibodies, corticosteroids, and others, were found to be effective against the novel COVID-19. Governments, private firms, researchers, and non-profit organizations are working hard to create a COVID-19 vaccine. In addition to the new medicines and old drug clinical testing, SARS-CoV-2 vaccines must also be designed and developed. Moreover, positive news in the development of vaccines suggests that new vaccines will be available on the market soon and a bowl of immunity against this virus can be established, thus limiting the spread and eradication of this deadly virus from the surface of the world as with so many viruses.
... In fact, a wide variety of drug screening assays are currently being conducted to explore the potential efficacy of new and old molecules in SARS-CoV-2. [3][4][5] In a randomized clinical trial of 299 adults with moderate or severe ARDS due to COVID-19, dexamethasone associated with standard care compared to standard care alone significantly increased the number of days alive and without mechanical ventilation during the first 28 days. Dexamethasone was not associated with an increased risk of adverse events in this population of critically ill COVID-19 patients. ...
The United States Centers for Disease Control and Prevention reported a rise in resistant infections after the coronavirus disease 2019 (COVID-19) pandemic started. How and if the pandemic contributed to antibiotic resistance in the larger population is not well understood. Wastewater treatment plants are good locations for environmental surveillance because they can sample entire populations. This study aimed to validate methods used for COVID-19 wastewater surveillance for bacterial targets and to understand how rising COVID-19 cases from October 2020 to February 2021 in Portugal (PT) and King County, Washington contributed to antibiotic resistance genes in wastewater. Primary influent wastewater was collected from two treatment plants in King County and five treatment plants in PT, and hospital effluent was collected from three hospitals in PT. Genomic extracts were tested with the quantitative polymerase chain reaction for antibiotic resistance genes conferring resistance against antibiotics under threat. Random-effect models were fit for log-transformed gene abundances to assess temporal trends. All samples collected tested positive for multiple resistance genes. During the sampling period, mecA statistically significantly increased in King County and PT. No statistical evidence exists of correlation between samples collected in the same Portuguese metro area.
Mesenchymal Stem Cells (MSCs) are being investigated as a treatment for a novel viral disease owing to their immunomodulatory, anti-inflammatory, tissue repair and regeneration characteristics, however, the exact processes are unknown. MSC therapy was found to be effective in lowering immune system overactivation and increasing endogenous healing after SARS-CoV-2 infection by improving the pulmonary microenvironment. Many studies on mesenchymal stem cells have been undertaken concurrently, and we may help speed up the effectiveness of these studies by collecting and statistically analyzing data from them. Based on clinical trial information found on clinicaltrials. gov and on 16 November 2020, which includes 63 clinical trials in the field of patient treatment with COVID-19 using MSCs, according to the trend of increasing studies in this field, and with the help of meta-analysis studies, it is possible to hope that the promise of MSCs will one day be realized. The potential therapeutic applications of MSCs for COVID-19 are investigated in this study.
Background:
The pandemic caused by the novel coronavirus disease (COVID-19) since early 2020 is one of the most significant global health issues in history. Although there is currently no specific treatment for COVID-19, researchers have provided a whole array of potential treatments, both from the Western medicine approach, which is molecular target and pathogenesis based, and from the traditional Chinese medicine (TCM) approach, which is based on the exposure to toxins/pathogens and the balance of the body to combat them for recovery.
Objective:
The aim of this research is to find combinations of Western medicine and TCM that may offer better therapeutic efficacy synergystically with a better adverse events profile. The findings of the research may provide a new insight in the development of the treatment of COVID-19.
Methods:
From the Western medicine perspective, drugs target the mechanisms of viral infection, including the stages of viral entry (Arbidol, Camostat Mesylate, Convalescent Plasma therapy) and viral replication (Lopinavir/Ritonavir, Redemsivir, Ribavirin). Additional therapies target host defenses, preventing cytokine storms (Tocilizumab) and stimulating the immune system (Interferons). On the other hand, TCM also proposed a number of treatment methods for COVID-19 with new scientific approaches identifying their antiviral and immunomodulatory activities. The novel combination of Western medicine and TCM can be proposed by analyzing their respective molecular targets.
Results:
Although TCM is not generally accepted in the Western community because of the general lack of knowledge on their detailed mechanisms, studies and clinical trials suggest that TCM could be beneficial in combating COVID-19.
Conclusion:
Based on the principle of combining TCM and Western medicine, two combinations are tested effective in clinical trials, and three possible combinations that might be effective are proposed in the paper.
COVID‐19 is known to involve the nervous system, for which three pathways have been suggested: (i) retrograde through neurons, (ii) angiotensin‐converting enzyme 2 (ACE‐2) expression in neurons, and (iii) hematogenous dissemination. In addition, damage to the central nervous system is mediated by an indirect effect of the virus causing a cytokine storm. In this chapter, the pathophysiologic mechanism of the involvement of nervous system in COVID‐19 and also its clinical manifestations and the diagnostic and therapeutic approach to the neurologic complications is reviewed.
Novel coronavirus disease caused by the SARS-CoV-19 virus enters the host cell through the S-spike protein by binding to ACE-2. In December 2019, an outbreak of coronavirus originated from Wuhan, China and by the end of 2020, it was recorded in almost every part of the world including Italy, Germany, Iran, Spain, and also United states. This led to a Pandemic which was declared by World Health Organization on 11th March 2020. SARS-CoV-19 causes mild to moderate illness which leads to acute respiratory syndrome, by causing infection in the nose, sinuses, or upper throat. It can also affect the upper or lower respiratory tract and has caused millions of cases and deaths. Many diagnostic tests have been authorized by the WHO including Direct and Indirect tests. Due to the increase in the number of covid 19 cases, many medications were introduced as per the demands like anti-malarial drugs, anti-viral drugs, antibiotics, anti-inflammatory drugs, steroids, biological agents, etc. The SARS-CoV-2 has a spike protein on its surface that aids in the virus's attachment to and entry into human cells. To attach to the protein of SARS-spike-CoV-2 and stop the virus from infecting human cells, many monoclonal antibodies like Casirivimab, imdevimab, Tocilizumab, Sarilumab, Itolizumab, Siltuximab have been created. As monoclonal antibodies prevent viruses from entering cells and continuing to proliferate, as well as lowering viral loads and lowering the frequency of hospital visits, they can be used as an alternative to conventional therapies. Hence monoclonal antibody treatment can be considered an effective alternative treatment for treating SARS-CoV-2.
Tocilizumab is an interleukin (IL)‐6 receptor inhibitor that has been proposed as a therapeutic agent for treating coronavirus disease 2019 (COVID‐19). The aim of this umbrella review was to determine the efficacy of tocilizumab in treating COVID‐19, and to provide an overview of all systematic reviews on this topic. We systematically searched PubMed, Scopus, the Web of Science collection, the Cochrane library, Epistemonikos, and Google Scholar, as well as the medRxiv preprint server. These databases were searched up to 30 September 2021, using the following keywords: ‘SARS‐CoV‐2’, ‘COVID‐19’, ‘tocilizumab’, ‘RHPM‐1’, ‘systematic review’, and ‘meta‐analysis’. Studies were included if they were systematic reviews (with or without meta‐analysis) investigating the efficacy or safety of tocilizumab in confirmed COVID‐19 patients. The AMSTAR 2 checklist was used to assess quality of the included articles, while publication bias was examined using Egger's test. A total of 50 eligible systematic reviews were included. The pooled estimates showed significant reductions in clinical failure (risk ratio (RR) 0.75; 95% confidence interval (CI), 0.61–0.93), deaths (RR 0.78; 95%CI, 0.71–0.85) and the need for mechanical ventilation (RR 0.77; 95%CI, 0.64–0.92) for those receiving tocilizumab compared with the control group. Also, an emerging survival benefit was demonstrated for those who received tocilizumab, over those in the control group (adjusted hazard ratio (aHR) 0.52; 95%CI, 0.43–0.63). In addition, tocilizumab substantially increased the number of ventilator‐free days, compared with the control treatments (weighted mean difference (WMD) 3.38; 95%CI, 0.51–6.25). Furthermore, lymphocyte count (WMD 0.26 × 109/L; 95%CI, 0.14–0.37), IL‐6 (WMD 176.99 pg/mL; 95%CI, 76.34–277.64) and D‐dimer (WMD 741.08 ng/mL; 95%CI, 109.42–1372.75) were all significantly elevated in those receiving tocilizumab. However, the level of lactate dehydrogenase (LDH) (WMD −30.88 U/L; 95%CI, −51.52, −10.24) and C‐reactive protein (CRP) (WMD ‐104.83 mg/L; 95%CI, −133.21, −76.46) were both significantly lower after treatment with tocilizumab. Tocilizumab treatment reduced the risk of intubation, mortality and the length of hospital stay, without increasing the risk of superimposed infections in COVID‐19 patients. Therefore, tocilizumab can be considered an effective therapeutic agent for treating patients with COVID‐19.
Structural immunology of coronavirus
Background :To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started,
including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral
efficacy.
Methods: In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against
SARS-CoV-2.
Findings: First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-
CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model.
In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to
impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffu-
sion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxa-
nide in organs of interest were always below the in vitro EC50.
Interpretation: These preclinical results suggest, if directly applicable to humans, that the standard formulation and
dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.
Introduction Accepting the fact that public support is the best stride toward legitimating an activity or knowledge, we will clearly find out the importance of generalizing the archaeology, in general and visiting the Archaeological sites, in particular. The public natures of tourism along with people's innate interest in archaeology have made it possible. Of course, such general tendencies and approaches led to innovation of an effective and efficient principle in the World Tourism Organization (WTO) which considered the basic principle of the cultural tourism as application of the human cultural heritage and participation in its promotion and improvement Cabrini. 1 The same general comprehensive principle makes the relation between scientific and applied archaeology as an inevitable course to study cultural heritage and tourism. The modern approaches in the world scientific communities and holding periodical and regular conferences have made clear the importance of the problem. Since, the archaeological methods of archaeology and the ways for people to achieve the predetermined results have been considerable; archaeology has taken steps toward generalizing itself. However, it seems that the best step is relating archaeology to tourism. This paper attempts to explain characteristics and functions of the archaeological tourism in the road toward generalizing the archaeology knowledge. Purpose The purpose of this article is to emphasize the sustainable interaction between archeology and tourism. Areas of joint collaboration have led to the creation of a joint study field, "Archaeological Tourism". Archaeological tourism as a specialized field has features and functions that show the importance of the issue in the field of preservation and promotion of cultural heritage. Promotes tourism and minimizes the negative consequences of tourism development in heritage environments. Introduces people to cultural heritage; So that people have a protective view in the face of cultural heritage, rather than a destroyer. Method The research method is based on the purpose of the article of an applied type that aims to interaction archeology with tourism. Some of the thoughts of archaeologists who think only of the mere physical preservation of artifacts are in conflict with the motives of tourism and the purpose of the tourism being visited. The theoretical concepts of this research have been compiled in the form of a library and referring to the relevant theoretical foundations and the real problems, features and functions of this field have been compiled.
The coronavirus disease 2019 (COVID-19) pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has dramatically impacted the global healthcare systems, constantly challenging both research and clinical practice. Although it was initially believed that the SARS-CoV-2 infection is limited merely to the respiratory system, emerging evidence indicates that COVID-19 affects multiple other systems including the central nervous system (CNS). Furthermore, most of the published clinical studies indicate that the confirmed CNS inflammatory manifestations in COVID-19 patients are meningitis, encephalitis, acute necrotizing encephalopathy, acute transverse myelitis, and acute disseminated encephalomyelitis. In addition, the neuroinflammation along with accelerated neurosenescence and susceptible genetic signatures in COVID-19 patients might prime the CNS to neurodegeneration and precipitate the occurrence of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Thus, this review provides a critical evaluation and interpretive analysis of existing published preclinical as well as clinical studies on the key molecular mechanisms modulating neuroinflammation and neurodegeneration induced by the SARS-CoV-2. In addition, the essential age- and gender-dependent impacts of SARS-CoV-2 on the CNS of COVID-19 patients are also discussed.
Purpose of Review
Since the past year, the fast spread of coronavirus disease 2019 (COVID-19) has represented a global health threat, especially for cancer patients, that has required an urgent reorganization of clinical activities. Here, we will critically revise the profound impact that the pandemic has generated in lung cancer patients, as well the most significant challenges that oncologists have to face to maintain the highest possible standards in the management of lung cancer patients in the pandemic era.
Recent Findings
Evidences suggested a higher susceptibility and mortality of lung cancer patients due to COVID-19. The hard management of this patient population has been also due to the potential cross interference of anti-tumor drugs on SARS-Cov-2 infection and to the differential diagnosis between COVID-19 pneumonitis and drug-related pneumonitis.
Summary
COVID-19 pandemic has generated a profound reshaping of oncological activities and the development of recommendations by the oncology scientific community to prioritize anti-tumor treatments for lung cancer patients.
The aim of this manuscript is to discuss the practice of antenatal corticosteroids administration for fetal maturation in severe acute respiratory syndrome coronavirus 2 positive pregnant women. Recent high-quality evidence supports the use of dexamethasone in the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19). Randomized disease outcome data have identified an association between disease stage and treatment outcome. In contrast to patients with more severe forms who benefit from dexamethasone, patients with mild disease do not appear to improve and may even be harmed by this treatment. Therefore, indiscriminate usage of fluorinated corticosteroids for fetal maturation, regardless of disease trajectory, is unadvisable. Obstetrical care needs to be adjusted during the COVID-19 pandemic with careful attention paid to candidate selection and risk stratification.
Concurrent waves of Coronavirus disease, Ebola virus disease, avian influenza A and black fungus are jeopardizing the lives in some parts of Africa and Asia. From this point of view, this review aims to summarize both socio-economic and public health implications of these parallel outbreaks along with their best possible management approaches. Various online databases were used to collect the necessary information regarding these outbreaks. Based on the reports published and analyses done so far, the long-lasting damages caused by these simultaneous outbreaks on global socio-economical and public health status can be conceived from the past experiences of outbreaks, especially the COVID-19 pandemic. Moreover, prolonged restrictions by the local government may lead to food insecurity, global recession, and an enormous impact on the mental health of people of all ages, specifically in developing countries. Such overwhelming effects already have been reported to be declining national growth of the economy as well as increasing political insecurity and shortage of basic needs. Although various actions have already been taken including vaccination, clinical management, and further research, social distancing, and lockdown, etc. to improve the situation, the emerging variants and associated genetic mutations may make the containment difficult worsening the situation again. Considering the current mutational dynamics of the pathogens and the past experiences, perpetual preparedness along with updated clinical management backed by epidemiological studies and innovating scientific effort are inevitable to combat the simultaneous waves of multiple infectious diseases.
The global pandemic produced by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first appeared in Wuhan, China, in December 2019 and which then spread rapidly, made it difficult to find or develop effective medications for its prevention and treatment. Therefore, the first stage is necessitating the use of a precise and quick diagnostic method to detect SARS-CoV-2 infected patient followed by effective patient isolation and the commencement of early treatment, which can range from supportive therapy to specialised medications such corticosteroids, antiviral medications, antibiotics, and the recently introduced convalescent plasma. Despite the extraordinary developments in advanced medicinal system, no confirmed viable medicines exist at this time. Rapid research on SARS CoV-2 epidemiology has led to the discovery of certain new targets for prospective therapeutic treatments. Many therapeutic options have been evaluated, and clinical studies are proceeding at a breakneck speed. However, there is a lot of room for more study into finding cost-effective and safer medicines, vaccinations, and measures to ensuring that COVID-19 preventive and treatment programmes are available to everyone. The goal of this study is to compile all of the current advancements in the worldwide medical system in the fight against COVID-19.
This preliminary study is aimed at examining the growth rate of Covid-19 pandemic in Indonesia in a framework of a nationwide issue. Using a spreadsheet, this study generates time-series development of the disease from its early stage in March to the late of July 2020. The study focuses on the analysis of three indicators, namely the number of people confirmly infected, recovered, and dead, daily reported by the authorities to monitor the severe outbreak. A number of groups of people, such as people under observation (ODP), suspected (PDP), and with no symptoms (OTG) are excluded from selected indicators due to difficulties in detection of people accounted for in each group. Cases confirmed are given by the results of Polymerase Chain Reaction (PCR) tests from swab sampled and are not determined by those of rapid tests. The data were collected from The Ministry of Health, The Republic of Indonesia and National Agency for Disaster Relief (BNPB). We report findings on the effectiveness of a PSBB policy that includes physical and social distancing during different stages and the possible roles of four connected parameters, namely community resilience, goverment control, medical access and treatment, and economy recovery. From the data acquired and presented in separate curves, we analyse the growth rate of Covid-19 in Indonesia. Regarding distinct trends of the curves with an indication of a continuous transmission, we conclude that combined factors, involving ineffective implementation of the policy and a low community resilience make the infectious disease outbreak uncontrollable in some sense.
Objective
To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19).
Design
Multicentre, open label, randomised controlled trial.
Setting
16 government designated covid-19 treatment centres in China, 11 to 29 February 2020.
Participants
150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone).
Interventions
Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively).
Main outcome measure
Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone.
Results
Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval –10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events.
Conclusions
Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients.
Trial registration
ChiCTR2000029868.
SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), was first identified in December 2019 in Wuhan, China, and has since spread worldwide. On March 11, 2020, the World Health Organization declared COVID-19 a pandemic (1). That same day, the first confirmed COVID-19-associated fatality occurred in New York City (NYC). To identify confirmed COVID-19-associated deaths, defined as those occurring in persons with laboratory-confirmed SARS-CoV-2 infection, on March 13, 2020, the New York City Department of Health and Mental Hygiene (DOHMH) initiated a daily match between all deaths reported to the DOHMH electronic vital registry system (eVital) (2) and laboratory-confirmed cases of COVID-19. Deaths for which COVID-19, SARS-CoV-2, or an equivalent term is listed on the death certificate as an immediate, underlying, or contributing cause of death, but that do not have laboratory-confirmation of COVID-19 are classified as probable COVID-19-associated deaths. As of May 2, a total of 13,831 laboratory-confirmed COVID-19-associated deaths, and 5,048 probable COVID-19-associated deaths were recorded in NYC (3). Counting only confirmed or probable COVID-19-associated deaths, however, likely underestimates the number of deaths attributable to the pandemic. The counting of confirmed and probable COVID-19-associated deaths might not include deaths among persons with SARS-CoV-2 infection who did not access diagnostic testing, tested falsely negative, or became infected after testing negative, died outside of a health care setting, or for whom COVID-19 was not suspected by a health care provider as a cause of death. The counting of confirmed and probable COVID-19-associated deaths also does not include deaths that are not directly associated with SARS-CoV-2 infection. The objective of this report is to provide an estimate of all-cause excess deaths that have occurred in NYC in the setting of widespread community transmission of SARS-CoV-2. Excess deaths refer to the number of deaths above expected seasonal baseline levels, regardless of the reported cause of death. Estimation of all-cause excess deaths is used as a nonspecific measure of the severity or impact of pandemics (4) and public health emergencies (5). Reporting of excess deaths might provide a more accurate measure of the impact of the pandemic.
Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the corona virus disease 2019 (COVID-19) cases in China and has become a public health emergency of international concern1. Because angiotensin-converting enzyme 2 (ACE2) is the cell entry receptor of SARS-CoV5, we used transgenic mice bearing human ACE2 and infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant macrophages and lymphocytes into the alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, macrophages and alveolar epithelia. The phenomenon was not found in wild-type mice with SARS-CoV-2 infection. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. The mouse model with SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutics and vaccines as well as understanding the pathogenesis of COVID-19.
Significance
In patients with coronavirus disease 2019, a large number of T lymphocytes and mononuclear macrophages are activated, producing cytokines such as interleukin-6 (IL-6), which bind to the IL-6 receptor on the target cells, causing the cytokine storm and severe inflammatory responses in lungs and other tissues and organs. Tocilizumab, as a recombinant humanized anti-human IL-6 receptor monoclonal antibody, can bind to the IL-6 receptor with high affinity, thus preventing IL-6 itself from binding to its receptor, rendering it incapable of immune damage to target cells, and alleviating the inflammatory responses.
Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
Importance
Coronavirus disease 2019 (COVID-19) is a pandemic with no specific therapeutic agents and substantial mortality. It is critical to find new treatments.
Objective
To determine whether convalescent plasma transfusion may be beneficial in the treatment of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Design, Setting, and Participants
Case series of 5 critically ill patients with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment; Pao2/Fio2 <300; and mechanical ventilation. All 5 were treated with convalescent plasma transfusion. The study was conducted at the infectious disease department, Shenzhen Third People's Hospital in Shenzhen, China, from January 20, 2020, to March 25, 2020; final date of follow-up was March 25, 2020. Clinical outcomes were compared before and after convalescent plasma transfusion.
Exposures
Patients received transfusion with convalescent plasma with a SARS-CoV-2–specific antibody (IgG) binding titer greater than 1:1000 (end point dilution titer, by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer greater than 40 (end point dilution titer) that had been obtained from 5 patients who recovered from COVID-19. Convalescent plasma was administered between 10 and 22 days after admission.
Main Outcomes and Measures
Changes of body temperature, Sequential Organ Failure Assessment (SOFA) score (range 0-24, with higher scores indicating more severe illness), Pao2/Fio2, viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after convalescent plasma transfusion.
Results
All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. Following plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and Pao2/Fio2 increased within 12 days (range, 172-276 before and 284-366 after). Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2–specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion.
Conclusions and Relevance
In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spread across the globe resulting in a pandemic. At the time of this review, COVID-19 has been diagnosed in more than 200 000 patients and associated with over 8000 deaths (Centers for Disease Control and Prevention, World Health Organization).
On behalf of the Society of Infectious Diseases Pharmacists, we herein summarize the current evidence as of March 18, 2020 to provide guidance on potential COVID-19 treatment options. It is important to caution readers that new data emerges daily regarding clinical characteristics, treatment options, and outcomes for COVID-19. Optimized supportive care remains the mainstay of therapy, and the clinical efficacy for the subsequent agents is still under investigation.
Antimicrobial stewardship programs, including infectious diseases pharmacists and physicians, are at the forefront of COVID-19 emergency preparedness.
We encourage all readers to continue to assess clinical data as it emerges and share their experience within our community in a well-controlled, adequately powered fashion.
It has been known that, the novel Coronavirus, 2019-nCoV, which is considered similar to SARS-CoV and originated from Wuhan (China), invades human cells via the receptor angiotensin converting enzyme II (ACE2). Moreover, lung cells that have ACE2 expression may be the main target cells during 2019-nCoV infection. However, some patients also exhibit non-respiratory symptoms, such as kidney failure, implying that 2019-nCoV could also invade other organs. To construct a risk map of different human organs, we analyzed the single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems, including the respiratory, cardiovascular, digestive, and urinary systems. Through scRNA-seq data analyses, we identified the organs at risk, such as lung, heart, esophagus, kidney, bladder, and ileum, and located specific cell types (i.e., type II alveolar cells (AT2), myocardial cells, proximal tubule cells of the kidney, ileum and esophagus epithelial cells, and bladder urothelial cells), which are vulnerable to 2019-nCoV infection. Based on the findings, we constructed a risk map indicating the vulnerability of different organs to 2019-nCoV infection. This study may provide potential clues for further investigation of the pathogenesis and route of 2019-nCoV infection.
A novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused a large respiratory outbreak in Wuhan, China in December 2019, is currently spreading across many countries globally. Here, we show that a TMPRSS2-expressing VeroE6 cell line is highly susceptible to SARS-CoV-2 infection, making it useful for isolating and propagating SARS-CoV-2. Our results reveal that, in common with SARS- and Middle East respiratory syndrome-CoV, SARS-CoV-2 infection is enhanced by TMPRSS2.
Background:
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection.
Methods:
The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug's safety profile.
Results:
Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance.
Conclusions:
Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
In December 2019, health authorities in Wuhan, China, identified a cluster of pneumonia cases of unknown aetiology linked to the city's South China Seafood Market. Subsequent investigations revealed a novel coronavirus, SARS-CoV-2, as the causative agent now at the heart of a major outbreak. The rising case numbers have been accompanied by unprecedented public health action, including the wholesale isolation of Wuhan. Alongside this has been a robust scientific response, including early publication of the pathogen genome, and rapid development of highly specific diagnostics. This article will review the new knowledge of SARS-CoV-2 COVID-19 acute respiratory disease, and summarise its clinical features.
A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.
Objective
In this study we execute a rational screen to identify Chinese medical herbs that are commonly used in treating viral respiratory infections and also contain compounds that might directly inhibit 2019 novel coronavirus (2019-nCoV), an ongoing novel coronavirus that causes pneumonia.
Methods
There were two main steps in the screening process. In the first step we conducted a literature search for natural compounds that had been biologically confirmed as against sever acute respiratory syndrome coronavirus or Middle East respiratory syndrome coronavirus. Resulting compounds were cross-checked for listing in the Traditional Chinese Medicine Systems Pharmacology Database. Compounds meeting both requirements were subjected to absorption, distribution, metabolism and excretion (ADME) evaluation to verify that oral administration would be effective. Next, a docking analysis was used to test whether the compound had the potential for direct 2019-nCoV protein interaction. In the second step we searched Chinese herbal databases to identify plants containing the selected compounds. Plants containing 2 or more of the compounds identified in our screen were then checked against the catalogue for classic herbal usage. Finally, network pharmacology analysis was used to predict the general in vivo effects of each selected herb.
Results
Of the natural compounds screened, 13 that exist in traditional Chinese medicines were also found to have potential anti-2019-nCoV activity. Further, 125 Chinese herbs were found to contain 2 or more of these 13 compounds. Of these 125 herbs, 26 are classically catalogued as treating viral respiratory infections. Network pharmacology analysis predicted that the general in vivo roles of these 26 herbal plants were related to regulating viral infection, immune/inflammation reactions and hypoxia response.
Conclusion
Chinese herbal treatments classically used for treating viral respiratory infection might contain direct anti-2019-nCoV compounds.
Importance
In December 2019, novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
Objective
To describe the epidemiological and clinical characteristics of NCIP.
Design, Setting, and Participants
Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020.
Exposures
Documented NCIP.
Main Outcomes and Measures
Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked.
Results
Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 10⁹/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0).
Conclusions and Relevance
In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.
On 31 December 2019 the Wuhan Health Commission reported a cluster of atypical pneumonia cases that was linked to a wet market in the city of Wuhan, China. The first patients began experiencing symptoms of illness in mid-December 2019. Clinical isolates were found to contain a novel coronavirus with similarity to bat coronaviruses. As of 28 January 2020, there are in excess of 4,500 laboratory-confirmed cases, with > 100 known deaths. As with the SARS-CoV, infections in children appear to be rare. Travel-related cases have been confirmed in multiple countries and regions outside mainland China including Germany, France, Thailand, Japan, South Korea, Vietnam, Canada, and the United States, as well as Hong Kong and Taiwan. Domestically in China, the virus has also been noted in several cities and provinces with cases in all but one provinence. While zoonotic transmission appears to be the original source of infections, the most alarming development is that human-to-human transmission is now prevelant. Of particular concern is that many healthcare workers have been infected in the current epidemic. There are several critical clinical questions that need to be resolved, including how efficient is human-to-human transmission? What is the animal reservoir? Is there an intermediate animal reservoir? Do the vaccines generated to the SARS-CoV or MERS-CoV or their proteins offer protection against 2019-nCoV? We offer a research perspective on the next steps for the generation of vaccines. We also present data on the use of in silico docking in gaining insight into 2019-nCoV Spike-receptor binding to aid in therapeutic development. Diagnostic PCR protocols can be found at https://www.who.int/health-topics/coronavirus/laboratory-diagnostics-for-novel-coronavirus.
Coronaviruses are the well-known cause of severe respiratory, enteric and systemic infections in a wide range of hosts including man, mammals, fish, and avian. The scientific interest on coronaviruses increased after the emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) outbreaks in 2002-2003 followed by Middle East Respiratory Syndrome CoV (MERS-CoV). This decade’s first CoV, named 2019-nCoV, emerged from Wuhan, China, and declared as ‘Public Health Emergency of International Concern’ on January 30th, 2020 by the World Health Organization (WHO). As on February 4, 2020, 425 deaths reported in China only and one death outside China (Philippines). In a short span of time, the virus spread has been noted in 24 countries. The zoonotic transmission (animal-to-human) is suspected as the route of disease origin. The genetic analyses predict bats as the most probable source of 2019-nCoV though further investigations needed to confirm the origin of the novel virus. The ongoing nCoV outbreak highlights the hidden wild animal reservoir of the deadly viruses and possible threat of spillover zoonoses as well. The successful virus isolation attempts have made doors open for developing better diagnostics and effective vaccines helping in combating the spread of the virus to newer areas.
Since the SARS outbreak 18 years ago, a large number of severe acute respiratory syndrome-related coronaviruses (SARSr-CoV) have been discovered in their natural reservoir host, bats1–4. Previous studies indicated that some of those bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a novel coronavirus (2019-nCoV) which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started from 12 December 2019, has caused 2,050 laboratory-confirmed infections with 56 fatal cases by 26 January 2020. Full-length genome sequences were obtained from five patients at the early stage of the outbreak. They are almost identical to each other and share 79.5% sequence identify to SARS-CoV. Furthermore, it was found that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. The pairwise protein sequence analysis of seven conserved non-structural proteins show that this virus belongs to the species of SARSr-CoV. The 2019-nCoV virus was then isolated from the bronchoalveolar lavage fluid of a critically ill patient, which can be neutralized by sera from several patients. Importantly, we have confirmed that this novel CoV uses the same cell entry receptor, ACE2, as SARS-CoV.
Emerging infectious diseases, such as SARS and Zika, present a major threat to public health1–3. Despite intense research efforts, how, when and where new diseases appear are still the source of considerable uncertainly. A severe respiratory disease was recently reported in the city Wuhan, Hubei province, China. Up to 25th of January 2020, at least 1,975 cases have been reported since the first patient was hospitalized on the 12th of December 2019. Epidemiological investigation suggested that the outbreak was associated with a seafood market in Wuhan. We studied one patient who was a worker at the market, and who was admitted to Wuhan Central Hospital on 26th of December 2019 experiencing a severe respiratory syndrome including fever, dizziness and cough. Metagenomic RNA sequencing4 of a bronchoalveolar lavage fluid sample identified a novel RNA virus from the family Coronaviridae, designed here as WH-Human-1 coronavirus. Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) previously sampled from bats in China. This outbreak highlights the ongoing capacity of viral spill-over from animals to cause severe disease in humans.
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed another clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).
Background:
An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geographically linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date.
Methods:
In this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan. Phylogenetic analysis of genetic sequences from these patients were done.
Findings:
From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36-66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3-6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6-10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats.
Interpretation:
Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions.
Funding:
The Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, Sanming Project of Medicine (Shenzhen), and High Level-Hospital Program (Guangdong Health Commission).
Background:
A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients.
Methods:
All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not.
Findings:
By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα.
Interpretation:
The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies.
Funding:
Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
The recent emergence of a novel coronavirus (2019‐nCoV), which is causing an outbreak of unusual viral pneumonia in patients in Wuhan, a central city in China, is another warning of the risk of CoVs posed to public health. In this minireview, we provide a brief introduction of the general features of CoVs and describe diseases caused by different CoVs in humans and animals. This review will help understand the biology and potential risk of CoVs that exist in richness in wildlife such as bats.
Highlights
• The general features of coronaviruses are introduced.
• The risk of emerging coronaviruses including the 2019‐nCoV is described.
• The genome structure and replication mechanism of coronaviruses are provided.
• The diseases caused by the major coronaviruses are listed.
In a large trial, a cheap and widely available steroid cut deaths by one-third among patients critically ill with COVID-19. In a large trial, a cheap and widely available steroid cut deaths by one-third among patients critically ill with COVID-19. Dexamethasone anti-inflammatory steroid tablets
Background
Mesenchymal stem cells (MSCs) are known to possess significant immunosuppressive properties, and their use in refractory SLE is supported by promising safety and efficacy in autoimmune animal models and human trials. We conducted this phase I open-label study to test the hypothesis that a single infusion of human allogeneic umbilical cord-derived MSCs (IND 16377) is safe when added to standard-of-care therapy for active SLE. The primary safety outcome is frequency of Grade 3 or higher adverse events (AEs) by Week 24. The primary efficacy outcome is change in SLE disease activity between Baseline and Week 24 measured by SLEDAI score and prednisone dose.
Methods
Patients (n=6) with active SLE (SLEDAI ≥6) who signed informed consent and met all inclusion and exclusion criteria sequentially received 1 × 10⁶ cells/kg umbilical cord-derived MSCs given as an IV infusion in Plasma-Lyte A solution. Post-infusion, Week 1 and 2 safety data from each participant was reviewed by the Data Safety Monitoring Board prior to enrolling the next patient. Primary safety and efficacy endpoints were determined at Week 24. Each patient is followed for a total of 52 weeks.
Results
Table 1 summarizes the demographics, visit SLEDAI scores, number of serious and non-serious adverse events (SAEs, AEs). The 6th participant completed their Week 24 visit on April 11, 2018. To date, there has been 1 SAE, deemed not unexpected and not attributed to investigational product. No non-serious AEs higher than Grade 2 by NCI-CTCAE scoring were reported. The SAE was prolonged hospitalization following a partial dose infusion of rituximab IV leading to anaphylaxis. Rituximab was started for persistent SLE disease activity (patient dropped out of the study after Week 8) and was given in the hospital ICU setting due to her prior history of anaphylaxis to Tween (polyethoxylated surfactant found in IV and SQ medications). Anaphylaxis resulted in a prolonged hospital stay of 2 days, resolving with treatment without sequelae. The SAE was attributed to her known allergy to ingredients in the rituximab infusion and deemed unrelated to the MSCs that she received several months earlier. The AEs ‘possibly’ attributable to the investigational product were Grade 2 nausea, Grade 2 tachycardia, and Grade 1 flushing with Grade 1 toe paresthesias – all of which resolved without sequelae.Among the 5 patients who completed their Week 24 evaluations, all showed improved SLE activity (mean SLEDAI score 8.6±1.9 at Baseline improved to 2.6±2.8 at Week 24) with stable or lower doses of prednisone and stable background immunosuppressants. Mean physician global assessment (PGA) scores also improved from 1.71±0.48 at Baseline to 0.32±0.17 at Week 24.
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Abstract CT-04 Table 1
Conclusions
A single-dose of umbilical cord-derived MSCs was safe and well-tolerated in this open-label phase I trial for 6 patients with active SLE. Initial efficacy data for MSCs in SLE appears promising and will be further tested in a larger controlled trial.
Acknowledgements
We would like to thank all of the study participants for their time and commitment to the study. This research study was supported by grants from the Lupus Foundation of America and the National Institutes of Health: National Institute of Allergy and Infectious Diseases (R34 AI114453) and the South Carolina Clinical and Translational Research (SCTR) Institute at the Medical University of South Carolina (UL1 RR029881).
Trial registration
NCT 03171194
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and rapidly spread worldwide. To prevent SARS-CoV-2 dissemination, understanding the in vivo characteristics of SARS-CoV-2 is a high priority. We report a ferret model of SARS-CoV-2 infection and transmission that recapitulates aspects of human disease. SARS-CoV-2-infected ferrets exhibit elevated body temperatures and virus replication. Although fatalities were not observed, SARS-CoV-2-infected ferrets shed virus in nasal washes, saliva, urine, and feces up to 8 days post-infection. At 2 days post-contact, SARS-CoV-2 was detected in all naive direct contact ferrets. Furthermore, a few naive indirect contact ferrets were positive for viral RNA, suggesting airborne transmission. Viral antigens were detected in nasal turbinate, trachea, lungs, and intestine with acute bronchiolitis present in infected lungs. Thus, ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.
Background
Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads.
Patients and methods
French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point.
Results
Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms.
Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination.
Conclusion
Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
Background:
No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.
Methods:
We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.
Results:
A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.
Conclusions:
In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
Background
Corona Virus Disease 2019 (COVID-19) due to the 2019 novel coronavirus (SARS-CoV-2) emerged in Wuhan city and rapidly spread throughout China. We aimed to compare arbidol and lopinavir/ritonavir(LPV/r) treatment for patients with COVID-19 with LPV/r only.
Methods
In this retrospective cohort study, we included adults (age≥18years) with laboratory-confirmed COVID-19 without Invasive ventilation, diagnosed between Jan 17, 2020, and Feb 13, 2020. Patients, diagnosed after Jan 17, 2020, were given oral arbidol and LPV/r in the combination group and oral LPV/r only in the monotherapy group for 5–21 days. The primary endpoint was a negative conversion rate of coronavirus from the date of COVID-19 diagnosis(day7, day14), and assessed whether the pneumonia was progressing or improving by chest CT (day7).
Results
We analyzed 16 patients who received oral arbidol and LPV/r in the combination group and 17 who oral LPV/r only in the monotherapy group, and both initiated after diagnosis. Baseline clinical, laboratory, and chest CT characteristics were similar between groups. The SARS-CoV-2 could not be detected for 12(75%) of 16 patients’ nasopharyngeal specimens in the combination group after seven days, compared with 6 (35%) of 17 in the monotherapy group (p<0•05). After 14 days, 15 (94%) of 16 and 9 (52•9%) of 17, respectively, SARS-CoV-2 could not be detected (p<0•05). The chest CT scans were improving for 11(69%) of 16 patients in the combination group after seven days, compared with 5(29%) of 17 in the monotherapy group (p<0•05).
Conclusion
In patients with COVID-19, the apparent favorable clinical response with arbidol and LPV/r supports further LPV/r only.
Purpose
COVID-19 (coronavirus disease 2019) is a public health emergency of international concern. As of this time, there is no known effective pharmaceutical treatment, although it is much needed for patient contracting the severe form of the disease. The aim of this systematic review was to summarize the evidence regarding chloroquine for the treatment of COVID-19.
Methods
PubMed, EMBASE, and three trial Registries were searched for studies on the use of chloroquine in patients with COVID-19.
Results
We included six articles (one narrative letter, one in-vitro study, one editorial, expert consensus paper, two national guideline documents) and 23 ongoing clinical trials in China. Chloroquine seems to be effective in limiting the replication of SARS-CoV-2 (virus causing COVID-19) in vitro.
Conclusions
There is rationale, pre-clinical evidence of effectiveness and evidence of safety from long-time clinical use for other indications to justify clinical research on chloroquine in patients with COVID-19. However, clinical use should either adhere to the Monitored Emergency Use of Unregistered Interventions (MEURI) framework or be ethically approved as a trial as stated by the World Health Organization. Safety data and data from high-quality clinical trials are urgently needed.
The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
At the time of writing this commentary (February 2020), the coronavirus COVID‐19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined. Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed. Developing vaccines against the SARS‐CoV‐2 virus may take many months. Moreover, vaccines based on viral‐encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new Influenza virus strains emerge every year, requiring new immunizations. A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS‐CoV‐2 virus infections. This idea is based on observations that the angiotensin‐converting enzyme 2 (ACE2) very likely serves as the binding site for SARS‐CoV‐2, the strain implicated in the current COVID‐19 epidemic, similarly to strain SARS‐CoV implicated in the 2002–2003 SARS epidemic. This commentary elaborates on the idea of considering AT1R blockers as tentative treatment for SARS‐CoV‐2 infections, and proposes a research direction based on datamining of clinical patient records for assessing its feasibility.
Infection by RNA viruses such as human immunodeficiency virus (HIV)-1, influenza, and dengue virus (DENV) represent a major burden for human health worldwide. Although RNA viruses replicate in the infected host cell cytoplasm, the nucleus is central to key stages of the infectious cycle of HIV-1 and Influenza, and an important target of DENV nonstructural protein 5 (NS5) in limiting the host antiviral response. We previously identified the small molecule ivermectin as an inhibitor of HIV-1 integrase nuclear entry, subsequently showing ivermectin could inhibit DENV NS5 nuclear import, as well as limit infection by viruses such as HIV-1 and DENV. We show here that ivermectin's broad spectrum antiviral activity relates to its ability to target the host importin (IMP) α/β1 nuclear transport proteins responsible for nuclear entry of cargoes such as integrase and NS5. We establish for the first time that ivermectin can dissociate the preformed IMPα/β1 heterodimer, as well as prevent its formation, through binding to the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity. We show that ivermectin inhibits NS5-IMPα interaction in a cell context using quantitative bimolecular fluorescence complementation. Finally, we show for the first time that ivermectin can limit infection by the DENV-related West Nile virus at low (μM) concentrations. Since it is FDA approved for parasitic indications, ivermectin merits closer consideration as a broad spectrum antiviral of interest.
The coronavirus (CoV) epidemic that began in China in December 2019 follows earlier epidemics of severe acute respiratory syndrome CoV in China and Middle East respiratory syndrome CoV in Saudi Arabia. The full genome of the 2019 novel coronavirus (2019-nCoV) has now been shared, and data have been gathered from several case series. As of February 11, 2020, there have been 45,182 laboratory-confirmed cases, the vast majority in China, with 1115 deaths, for an overall case-fatality rate of 2.5%. Cases have been confirmed in 27 countries. On average, each patient infects 2.2 other people. Symptomatic infection appears to predominantly affect adults, with a 5-day estimated incubation period between infection and symptom onset. The most common presenting symptoms are fever, cough, dyspnea, and myalgias and/or fatigue. All cases reported to date have shown radiographic evidence of pneumonia. 2019-nCoV is diagnosed by real-time reverse transcriptase polymerase chain reaction. Treatment is largely supportive, with regimens including antiviral therapy. Corticosteroids are not routinely recommended. Hand hygiene, prompt identification and isolation of suspect patients, and appropriate use of personal protective equipment are the most reliable methods to contain the epidemic.
The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.
Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously provisionally named 2019 novel coronavirus or 2019-nCoV) disease (COVID-19) in China at the end of 2019, has caused a large global outbreak and a major public health issue. As of February 11, 2020, data from the WHO has shown that more than 43,000 confirmed cases have been identified in 28 countries/regions, with more than 99% of the cases being detected in China. On January 30, 2020, WHO has declared COVID-19 as the sixth public health emergency of international concern. The SARS-CoV-2 is closely related to two bat-derived severe acute respiratory syndrome-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21. It is spread by human-to-human transmission via droplets or direct contact, and infection has been estimated to have mean incubation period of 6.4 days and a basic reproduction number of 2.24-3.58. Among the patients with pneumonia caused by the SARS-CoV-2 (novel coronavirus pneumonia or Wuhan pneumonia), fever was the most common symptom, followed by cough. Bilateral lung involvement with ground glass opacity was the most common finding from computerized tomography images of the chest. Although the one case of SARS-CoV-2 pneumonia in the United States responding well to remdesivir, which is now undergoing a clinical trial in China. Currently, controlling infection to prevent the spread of the SARS-CoV-2 is the primary intervention being used. However, public health authorities should keep monitoring the situation closely, as the more we can learn about this novel virus and its associated outbreak, the better we can respond.
An outbreak of novel coronavirus (2019-nCoV) that began in Wuhan, China, has spread rapidly, with cases now confirmed in multiple countries. We report the first case of 2019-nCoV infection confirmed in the United States and describe the identification, diagnosis, clinical course, and management of the case, including the patient's initial mild symptoms at presentation with progression to pneumonia on day 9 of illness. This case highlights the importance of close coordination between clinicians and public health authorities at the local, state, and federal levels, as well as the need for rapid dissemination of clinical information related to the care of patients with this emerging infection.
Background:
In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed.
Methods:
We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus.
Findings:
The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.
Interpretation:
2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation.
Funding:
National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
Background:
In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia.
Methods:
In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020.
Findings:
Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure.
Interpretation:
The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection.
Funding:
National Key R&D Program of China.