Immunomodulatory Drugs in the Management of SARS-CoV-2.
TL;DR: Viable treatment options for SARS-CoV-2 using immunomodulatory drugs and at what stage of the condition they may be beneficial are discussed.
Abstract: With the onset of the global pandemic in 2020 of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), there has been increasing research activity around certain disease-modifying drugs that are used for the management of inflammatory disorders such as rheumatoid arthritis, spondyloarthrosis, psoriatic arthritis, systemic lupus erythematosus, and inflammatory bowel disease for managing coronavirus symptoms. In the conditions mentioned, many people are on long-term treatment with agents including hydroxychloroquine, tumor necrosis factor alpha (TNFα) inhibitor drugs, other biologic agents such as monoclonal antibodies to IL-6 and Janus kinase inhibitors including baricitinib and tofacitinib, which are used to control inflammatory responses in their respective auto-immune condition. There is emerging data that immunomodulatory drugs could be protective at reducing certain features of SARS-CoV-2 and improving recovery. In addition, it is important to understand if subjects being treated with the immunomodulatory agents described have a less severe SARS-CoV-2 infection, as they are deemed some protection from their immunomodulatory treatment, or if they develop infections similar to non-immunocompromised patients. There is a huge unmet clinical need to advise patients responsibly about whether they should remain on their immunomodulatory treatment or not in light of Covid-19 infection. In this article we will discuss potential treatment options for SARS-CoV-2 using immunomodulatory drugs and at what stage of the condition they may be beneficial. Viable treatment options during the global coronavirus pandemic are a much-needed and an intensely active area of research.
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TL;DR: In this article, the authors discuss which viral elements are used in COVID-19 vaccine candidates, why they might act as good targets for the immune system and the implications for protective immunity.
Abstract: Vaccines are urgently needed to control the coronavirus disease 2019 (COVID-19) pandemic and to help the return to pre-pandemic normalcy. A great many vaccine candidates are being developed, several of which have completed late-stage clinical trials and are reporting positive results. In this Progress article, we discuss which viral elements are used in COVID-19 vaccine candidates, why they might act as good targets for the immune system and the implications for protective immunity.
726 citations
TL;DR: In this article, the parent nucleoside of remdesivir, GS-441524, was shown to inhibit the replication of SARS-CoV-2 in Vero E6 and other cell lines.
Abstract: The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) At the time of this manuscript's publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases
74 citations
TL;DR: The parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells and supported that GS- 441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.
Abstract: The outbreak of coronavirus disease 2019 (COVID-19) rapidly spreads across worldwide and becomes a global pandemic. Remdesivir is the only COVID-19 treatment approved by U.S. Food and Drug Administration (FDA); however, its effectiveness is still under questioning as raised by the results of a large WHO Solidarity Trial. Herein, we report that the parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells. It exhibits good plasma distribution and longer half-life (t1/2=4.8h) in rat PK study. GS-441524 is highly efficacious against SARS-CoV-2 in AAV-hACE2 transduced mice and murine hepatitis virus (MHV) in mice, reducing the viral titers in CoV-attacked organs, without noticeable toxicity. Given that GS-441524 was the predominant metabolite of remdesivir in the plasma, the anti-COVID-19 effect of remdesivir may partly come from the effect of GS-441524. Our results also supported that GS-441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.
52 citations
TL;DR: In this article, a literature exploration was made using PubMed, Embase, MEDLINE, Google scholar, and China National Knowledge Infrastructure databases to retrieve the most recent literature on the etiology, diagnostic markers, and the possible prophylactic and therapeutic options for the management of cytokine storm in patients hospitalized with COVID-19 disease.
Abstract: The COVID-19 pandemic constitutes an arduous global health challenge, and the increasing number of fatalities calls for the speedy pursuit of a remedy. This review emphasizes the changing aspects of the COVID-19 disease, featuring the cytokine storm's pathological processes. Furthermore, we briefly reviewed potential therapeutic agents that may modulate and alleviate cytokine storms. The literature exploration was made using PubMed, Embase, MEDLINE, Google scholar, and China National Knowledge Infrastructure databases to retrieve the most recent literature on the etiology, diagnostic markers, and the possible prophylactic and therapeutic options for the management of cytokine storm in patients hospitalized with COVID-19 disease. The causative agent, severe acute respiratory coronavirus-2 (SARS-CoV-2), continually threatens the efficiency of the immune system of the infected individuals. As the first responder, the innate immune system provides primary protection against COVID-19, affecting the disease's progression, clinical outcome, and prognosis. Evidence suggests that the fatalities associated with COVID-19 are primarily due to hyper-inflammation and an aberrant immune function. Accordingly, the magnitude of the release of pro-inflammatory cytokines such as interleukin (IL)-1, (IL-6), and tumor necrosis alpha (TNF-α) significantly differentiate between mild and severe cases of COVID-19. The early prediction of a cytokine storm is made possible by several serum chemistry and hematological markers. The prompt use of these markers for diagnosis and the aggressive prevention and management of a cytokine release syndrome is critical in determining the level of morbidity and fatality associated with COVID-19. The prophylaxis and the rapid treatment of cytokine storm by clinicians will significantly enhance the fight against the dreaded COVID-19 disease.
46 citations
TL;DR: Progress in developing COVID-19 vaccines is highlighted, especially for efficient vaccination of the older population, and a summary of immunomodulatory and immunotherapeutic approaches to ameliorate the outcome of CO VID-19 in older individuals is presented.
Abstract: The rapid worldwide spread of the COVID-19 pandemic, caused by the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in tens of millions of infections and over one million deaths. SARS-CoV-2 infection affects all age groups; however, those over 60 years old are affected more severely. Moreover, pre-existing co-morbidities result in higher COVID-19-associated mortality in the geriatric population. This article highlights the associated risk factors of SARS-CoV-2 infection in older people and progress in developing COVID-19 vaccines, especially for efficient vaccination of the older population. There is also a summary of immunomodulatory and immunotherapeutic approaches to ameliorate the outcome of COVID-19 in older individuals.
34 citations
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TL;DR: Re-analysis of data from a phase 3 randomised controlled trial of IL-1 blockade (anakinra) in sepsis, showed significant survival benefit in patients with hyperinflammation, without increased adverse events.
7,493 citations
"Immunomodulatory Drugs in the Manag..." refers background in this paper
...reported features of a cytokine storm syndrome in a subgroup of COVID-19 patients (5)....
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...It is now apparent that SARS-CoV-2 infection has two clear clinical phases of infection: the former, which involves the viral infection and replication (4) and the inflammatory phase which often leads to rapid deterioration and worsening respiratory symptoms, requiring hospital admission in many cases to avoid deterioration (4, 5)....
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...It has been proposed that by screening for hyperinflammation to identify at risk groups, targeted immunomodulation could improve mortality (5)....
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TL;DR: This study evaluated the antiviral efficiency of five FAD-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir and favipiravir against a clinical isolate of 2019-nCoV in vitro.
Abstract: Dear Editor, In December 2019, a novel pneumonia caused by a previously unknown pathogen emerged in Wuhan, a city of 11 million people in central China. The initial cases were linked to exposures in a seafood market in Wuhan. As of January 27, 2020, the Chinese authorities reported 2835 confirmed cases in mainland China, including 81 deaths. Additionally, 19 confirmed cases were identified in Hong Kong, Macao and Taiwan, and 39 imported cases were identified in Thailand, Japan, South Korea, United States, Vietnam, Singapore, Nepal, France, Australia and Canada. The pathogen was soon identified as a novel coronavirus (2019-nCoV), which is closely related to sever acute respiratory syndrome CoV (SARS-CoV). Currently, there is no specific treatment against the new virus. Therefore, identifying effective antiviral agents to combat the disease is urgently needed. An efficient approach to drug discovery is to test whether the existing antiviral drugs are effective in treating related viral infections. The 2019-nCoV belongs to Betacoronavirus which also contains SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). Several drugs, such as ribavirin, interferon, lopinavir-ritonavir, corticosteroids, have been used in patients with SARS or MERS, although the efficacy of some drugs remains controversial. In this study, we evaluated the antiviral efficiency of five FAD-approved drugs including ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and two well-known broad-spectrum antiviral drugs remdesivir (GS5734) and favipiravir (T-705) against a clinical isolate of 2019nCoV in vitro. Standard assays were carried out to measure the effects of these compounds on the cytotoxicity, virus yield and infection rates of 2019-nCoVs. Firstly, the cytotoxicity of the candidate compounds in Vero E6 cells (ATCC-1586) was determined by the CCK8 assay. Then, Vero E6 cells were infected with nCoV2019BetaCoV/Wuhan/WIV04/2019 at a multiplicity of infection (MOI) of 0.05 in the presence of varying concentrations of the test drugs. DMSO was used in the controls. Efficacies were evaluated by quantification of viral copy numbers in the cell supernatant via quantitative real-time RT-PCR (qRT-PCR) and confirmed with visualization of virus nucleoprotein (NP) expression through immunofluorescence microscopy at 48 h post infection (p.i.) (cytopathic effect was not obvious at this time point of infection). Among the seven tested drugs, high concentrations of three nucleoside analogs including ribavirin (half-maximal effective concentration (EC50)= 109.50 μM, halfcytotoxic concentration (CC50) > 400 μM, selectivity index (SI) > 3.65), penciclovir (EC50= 95.96 μM, CC50 > 400 μM, SI > 4.17) and favipiravir (EC50= 61.88 μM, CC50 > 400 μM, SI > 6.46) were required to reduce the viral infection (Fig. 1a and Supplementary information, Fig. S1). However, favipiravir has been shown to be 100% effective in protecting mice against Ebola virus challenge, although its EC50 value in Vero E6 cells was as high as 67 μM, suggesting further in vivo studies are recommended to evaluate this antiviral nucleoside. Nafamostat, a potent inhibitor of MERS-CoV, which prevents membrane fusion, was inhibitive against the 2019-nCoV infection (EC50= 22.50 μM, CC50 > 100 μM, SI > 4.44). Nitazoxanide, a commercial antiprotozoal agent with an antiviral potential against a broad range of viruses including human and animal coronaviruses, inhibited the 2019-nCoV at a low-micromolar concentration (EC50= 2.12 μM; CC50 > 35.53 μM; SI > 16.76). Further in vivo evaluation of this drug against 2019-nCoV infection is recommended. Notably, two compounds remdesivir (EC50= 0.77 μM; CC50 > 100 μM; SI > 129.87) and chloroquine (EC50= 1.13 μM; CC50 > 100 μM, SI > 88.50) potently blocked virus infection at low-micromolar concentration and showed high SI (Fig. 1a, b). Remdesivir has been recently recognized as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV) infection in cultured cells, mice and nonhuman primate (NHP) models. It is currently under clinical development for the treatment of Ebola virus infection. Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination. Our time-ofaddition assay showed remdesivir functioned at a stage post virus entry (Fig. 1c, d), which is in agreement with its putative antiviral mechanism as a nucleotide analogue. Warren et al. showed that in NHP model, intravenous administration of 10mg/kg dose of remdesivir resulted in concomitant persistent levels of its active form in the blood (10 μM) and conferred 100% protection against Ebola virus infection. Our data showed that EC90 value of remdesivir against 2019-nCoV in Vero E6 cells was 1.76 μM, suggesting its working concentration is likely to be achieved in NHP. Our preliminary data (Supplementary information, Fig. S2) showed that remdesivir also inhibited virus infection efficiently in a human cell line (human liver cancer Huh-7 cells), which is sensitive to 2019-nCoV. Chloroquine, a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broadspectrum antiviral drug. Chloroquine is known to block virus infection by increasing endosomal pH required for virus/ cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at postentry stages of the 2019-nCoV infection in Vero E6 cells (Fig. 1c, d). Besides its antiviral activity, chloroquine has an immune-modulating activity, which may synergistically enhance its antiviral effect in vivo. Chloroquine is widely distributed in the whole body, including lung, after oral administration. The EC90 value of chloroquine against the 2019-nCoV in Vero
5,660 citations
"Immunomodulatory Drugs in the Manag..." refers background in this paper
...Recently, chloroquine was identified as having potent activity against SARS-CoV-2 (27)....
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TL;DR: This study conducted a retrospective multicenter study of 68 death cases and 82 discharged cases with laboratory-confirmed infection of SARS-CoV-2 and confirmed that some patients died of fulminant myocarditis, which is characterized by a rapid progress and a severe state of illness.
Abstract: Dear Editor, The rapid emergence of COVID-19 in Wuhan city, Hubei Province, China, has resulted in thousands of deaths [1]. Many infected patients, however, presented mild flu-like symptoms and quickly recover [2]. To effectively prioritize resources for patients with the highest risk, we identified clinical predictors of mild and severe patient outcomes. Using the database of Jin Yin-tan Hospital and Tongji Hospital, we conducted a retrospective multicenter study of 68 death cases (68/150, 45%) and 82 discharged cases (82/150, 55%) with laboratory-confirmed infection of SARS-CoV-2. Patients met the discharge criteria if they had no fever for at least 3 days, significantly improved respiratory function, and had negative SARS-CoV-2 laboratory test results twice in succession. Case data included demographics, clinical characteristics, laboratory results, treatment options and outcomes. For statistical analysis, we represented continuous measurements as means (SDs) or as medians (IQRs) which compared with Student’s t test or the Mann–Whitney–Wilcoxon test. Categorical variables were expressed as numbers (%) and compared by the χ2 test or Fisher’s exact test. The distribution of the enrolled patients’ age is shown in Fig. 1a. There was a significant difference in age between the death group and the discharge group (p < 0.001) but no difference in the sex ratio (p = 0.43). A total of 63% (43/68) of patients in the death group and 41% (34/82) in the discharge group had underlying diseases (p = 0.0069). It should be noted that patients with cardiovascular diseases have a significantly increased risk of death when they are infected with SARS-CoV-2 (p < 0.001). A total of 16% (11/68) of the patients in the death group had secondary infections, and 1% (1/82) of the patients in the discharge group had secondary infections (p = 0.0018). Laboratory results showed that there were significant differences in white blood cell counts, absolute values of lymphocytes, platelets, albumin, total bilirubin, blood urea nitrogen, blood creatinine, myoglobin, cardiac troponin, C-reactive protein (CRP) and interleukin-6 (IL-6) between the two groups (Fig. 1b and Supplementary Table 1). The survival times of the enrolled patients in the death group were analyzed. The distribution of survival time from disease onset to death showed two peaks, with the first one at approximately 14 days (22 cases) and the second one at approximately 22 days (17 cases) (Fig. 1c). An analysis of the cause of death was performed. Among the 68 fatal cases, 36 patients (53%) died of respiratory failure, five patients (7%) with myocardial damage died of circulatory failure, 22 patients (33%) died of both, and five remaining died of an unknown cause (Fig. 1d). Based on the analysis of the clinical data, we confirmed that some patients died of fulminant myocarditis. In this study, we first reported that the infection of SARS-CoV-2 may cause fulminant myocarditis. Given that fulminant myocarditis is characterized by a rapid progress and a severe state of illness [3], our results should alert physicians to pay attention not only to the symptoms of respiratory dysfunction but also the symptoms of cardiac injury. *Correspondence: songsingsjx@sina.com 4 Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China Full author information is available at the end of the article
3,868 citations
"Immunomodulatory Drugs in the Manag..." refers background in this paper
...It is now apparent that SARS-CoV-2 infection has two clear clinical phases of infection: the former, which involves the viral infection and replication (4) and the inflammatory phase which often leads to rapid deterioration and worsening respiratory symptoms, requiring hospital admission in many cases to avoid deterioration (4, 5)....
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...Although corticosteroids are not routinely recommended and may exacerbate COVID-19-associated lung injury (4), in hyperinflammation, immunosuppression is likely to be beneficial....
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TL;DR: Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.
Abstract: After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways. Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab. Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.
2,204 citations
"Immunomodulatory Drugs in the Manag..." refers background in this paper
...A recent retrospective study reported outcomes for 21 patients in China (7)....
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...Keywords: SARS-CoV-2, hyperinflammation, biologics, cytokines, immunomodulators INTRODUCTION The global pandemic of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which originated in China in late 2019, has spread rapidly throughout the world to become a global pandemic....
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...In this uncontrolled study, 21 patients with severe or critical Covid-19 pneumonia were treated with tocilizumab 400mg intravenously (7)....
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TL;DR: While men and women have the same prevalence, men with COVID-19 are more at risk for worse outcomes and death, independent of age.
Abstract: Objective: The recent outbreak of Novel Coronavirus Disease (COVID-19) is reminiscent of the SARS outbreak in 2003. We aim to compare the severity and mortality between male and female patients with COVID-19 or SARS. Study Design and Setting: We extracted the data from: (1) a case series of 43 hospitalized patients we treated, (2) a public data set of the first 37 cases of patients who died of COVID-19 and 1,019 patients who survived in China, and (3) data of 524 patients with SARS, including 139 deaths, from Beijing in early 2003. Results: Older age and a high number of comorbidities were associated with higher severity and mortality in patients with both COVID-19 and SARS. Age was comparable between men and women in all data sets. In the case series, however, men's cases tended to be more serious than women's (P = 0.035). In the public data set, the number of men who died from COVID-19 is 2.4 times that of women (70.3 vs. 29.7%, P = 0.016). In SARS patients, the gender role in mortality was also observed. The percentage of males were higher in the deceased group than in the survived group (P = 0.015). Conclusion: While men and women have the same prevalence, men with COVID-19 are more at risk for worse outcomes and death, independent of age.
1,506 citations