In Silico Drug Repositioning for COVID-19: Progress and Challenges

he COVID-19 pandemic caused by SARS-CoV-2 has shown a rapid increase in the number of infected patients with a remarkable mortality rate, making it a global public health concern. Because there is currently no specific anti-viral drug for the treatment of COVID-19, repurposing of already approved drugs for other diseases may be explored. Drug repurposing has become a promising approach due to the opportunity to reduce development timelines and overall costs. In this chapter, we will discuss various computational drug repositioning strategies, the current COVID-19 treatment scenario, and challenges to the correct interpretation of existing preclinical/clinical evidence, as well as the generation of new evidence related to drug repurposing. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

[Early use of tocilizumab in hospitalized patients with severe and critical COVID-19 in the Province of Buenos Aires: a multicentric study]

INTRODUCTION: Tocilizumab (TCZ), an IL-6 receptor antagonist monoclonal antibody is warranted in severe and critically-ill COVID-19 patients. The objective was to evaluate 28-day mortality of patients with severe or critical COVID-19 treated with early vs delayed TCZ. METHODS: Multicenter, retrospective cohort study including patients >18 years hospitalized between 7/1/2021-8/1/2022 with confirmed COVID-19, with 5, 6 and 7 points of WHO Ordinal Initial Severity Scale [SS]. Early or late administration was considered if TCZ was administered before or after 48 hours from admission. Outcomes were 28-day mortality and change of SS. Factors related to 28-day mortality were evaluated with Cox regression. RESULTS: 266 patients were included, 159(60%) male;aged 58(+/- 15);frequent comorbidities were hypertension (42%), obesity (37%) and diabetes (27%). Seventy patients had a SS = 5 (Supplemental O2), 143 had SS = 6 (NIV/ HFNC), and 53 had SS = 7 (IMV). 28-day mortality was 42%(112/266);predictors were age, obesity, higher SS, days between hospitalization and TCZ administration, and fewer days between symptoms onset and TCZ. Mortality of SS 5, 6 and 7 was 26%, 39% and 72% respectively. Compared with baseline SS points, 76% and 62% of patients remained stable or improved on days 3 and 7 since TCZ administration. 28-day mortality was lower when TCZ was administered before 48 hours (39% vs 57%;p = 0.02;HR = 0.63;[0.41-0.99, p = 0.05]). DISCUSSION: This study supports the early use of TCZ in patients with severe or critical COVID-19.

COVID-19 in liver transplant recipients

Coronavirus disease 2019 (COVID-19), an infection caused by severe acute respiratory syndrome coronavirus-type 2 (SARS-CoV-2), has emerged as a serious threat to public health. Liver transplant (LT) recipients may be at increased risk of acquisition of SARS-CoV-2 infection and higher morbidity and mortality due to constant contact with health-care services, the use of immunosuppressants and frequent comorbidities. In the first part of this review we discuss (1) the epidemiology and risk factors for SARS-CoV-2 infection in LT recipients;(2) the clinical and laboratory features of COVID-19 in this specific population, highlighting differences in presenting signs and symptoms with respect to general populations and (3) the natural history and prognostic factors in LT recipients hospitalized with COVID-19, with particular focus on the possible role of immunosuppression. Thereafter, we review the potential therapeutic options for COVID-19 treatment and prevention. Specifically, we give an overview of current practice in immunosuppressant regimen changes, showing the potential benefits of this strategy, and explore safety and efficacy issues of currently approved drugs in LT recipients. The last topic is dedicated to the potential benefits and pitfalls of vaccination.Copyright © 2021 The Authors

The Early Detection of Fraudulent COVID-19 Products From Twitter Chatter: Data Set and Baseline Approach Using Anomaly Detection.

Background: Social media has served as a lucrative platform for spreading misinformation and for promoting fraudulent products for the treatment, testing, and prevention of COVID-19. This has resulted in the issuance of many warning letters by the US Food and Drug Administration (FDA). While social media continues to serve as the primary platform for the promotion of such fraudulent products, it also presents the opportunity to identify these products early by using effective social media mining methods. Objective: Our objectives were to (1) create a data set of fraudulent COVID-19 products that can be used for future research and (2) propose a method using data from Twitter for automatically detecting heavily promoted COVID-19 products early. Methods: We created a data set from FDA-issued warnings during the early months of the COVID-19 pandemic. We used natural language processing and time-series anomaly detection methods for automatically detecting fraudulent COVID-19 products early from Twitter. Our approach is based on the intuition that increases in the popularity of fraudulent products lead to corresponding anomalous increases in the volume of chatter regarding them. We compared the anomaly signal generation date for each product with the corresponding FDA letter issuance date. We also performed a brief manual analysis of chatter associated with 2 products to characterize their contents. Results: FDA warning issue dates ranged from March 6, 2020, to June 22, 2021, and 44 key phrases representing fraudulent products were included. From 577,872,350 posts made between February 19 and December 31, 2020, which are all publicly available, our unsupervised approach detected 34 out of 44 (77.3%) signals about fraudulent products earlier than the FDA letter issuance dates, and an additional 6 (13.6%) within a week following the corresponding FDA letters. Content analysis revealed misinformation, information, political, and conspiracy theories to be prominent topics. Conclusions: Our proposed method is simple, effective, easy to deploy, and does not require high-performance computing machinery unlike deep neural network-based methods. The method can be easily extended to other types of signal detection from social media data. The data set may be used for future research and the development of more advanced methods.

Identification of Clinical Response Predictors of Tocilizumab Treatment in Patients with Severe COVID-19 Based on Single-Center Experience.

Hyperinflammation in COVID-19 plays a crucial role in pathogenesis and severity; thus, many immunomodulatory agents are applied in its treatment. We aimed to identify good clinical response predictors of tocilizumab (TCZ) treatment in severe COVID-19, among clinical, laboratory, and radiological variables. We conducted a prospective, observational study with 120 patients with severe COVID-19 not improving despite dexamethasone (DEX) treatment. We used parametric and non-parametric statistics, univariate logistic regression, receiver operating characteristic (ROC) curves, and nonlinear factors tertile analysis. In total, 86 (71.7%) patients achieved the primary outcome of a good clinical response to TCZ. We identified forty-nine predictive factors with potential utility in patient selection and treatment monitoring. The strongest included time from symptom onset between 9 and 12 days, less than 70% of estimated radiological lung involvement, and lower activity of lactate dehydrogenase. Additional predictors were associated with respiratory function, vitamin D concentration, comorbidities, and inflammatory/organ damage biomarkers. Adverse events analysis proved the safety of such a regimen. Our study confirmed that using TCZ early in the hyperinflammatory phase, before severe respiratory failure development, is most beneficial. Considering the described predictive factors, employing simple and widely available laboratory, radiological, and clinical tools can optimize patient selection for immunomodulatory treatment with TCZ.

Patients with moderate to severe COVID-19 outcomes on remdesivir according to baseline 4C mortality score.

BACKGROUND: Remdesivir was the first antiviral to show clinical benefit in patients with moderate-to-severe COVID-19. Previous trials demonstrated a faster time to recovery in hospitalized patients treated with remdesivir vs placebo. Current guidelines recommend treatment with remdesivir based on hospitalization status, oxygen requirements, and time from symptom onset. However, other factors may be evaluated to determine disease severity and risk for progression. The 4C mortality score is a validated, eight variable score that may be used to categorize patients by mortality risk at the time of hospital admission for COVID pneumonia. The objective of this study was to determine if the 4C mortality score may be used to predict which patients with moderate to severe COVID-19 would benefit the most from remdesivir at the time of hospital admission. METHODS: This was a single-center retrospective cohort study comparing time to recovery among hospitalized patients with moderate-to-severe COVID-19 who were treated with remdesivir compared to those who were treated with standard of care (SOC). The primary outcome was time to recovery, defined as discharge from the hospital or no longer requiring supplemental oxygen, stratified by the 4C mortality score risk group. Secondary outcomes included in-hospital mortality, hospital length of stay, and time to recovery in patients who were started on remdesivir within 7 days from symptom onset vs after 7 days from symptom onset. A survival analysis was used to analyze time to recovery outcomes. RESULTS: Data was collected and analyzed for a total of 300 patients, of which 200 received remdesivir and 100 received SOC. Patients in the remdesivir group had a longer time to recovery compared to patients in the SOC group (6 days vs 4 days). This finding was driven by patients who were categorized to the intermediate risk and high risk mortality groups. Additionally, patients who received remdesivir had a longer length of hospital stay compared to those who received SOC (12 days vs 9 days). Remdesivir was not associated with an increased rate of adverse events. CONCLUSIONS: This study of patients admitted with moderate-to-severe COVID-19 found that patients who were treated with remdesivir had a longer time to recovery and a longer length of stay compared to those who received SOC. These findings add to the body of evidence questioning the benefit of remdesivir therapy among patients hospitalized with COVID-19.

nCovid19 - A consolidated review with emphasis on oral mucormycosis

The last 2 years has been highly tumultuous with the advent of the 2019 novel coronavirus disease (nCovid-19). This viral infection has been a global landmark event in the history of mankind with its standout characteristics such as high transmission rate, initial asymptomatic period, and unexpected systemic outcomes. The long-term damage of this disease is still being unraveled with a profound impact on the global economy and livelihood of millions as well. A literature search was performed with the following keywords - Coronavirus, COVID-19, SARS-CoV-2, 2019-nCoV, Mucormycosis, and Opportunistic infections - in PUBMED/MEDLINE database to assimilate articles/case reports/books about nCovid19 and mucormycosis. nCovid19 data were collected from the Centers for Disease Control and Prevention and Ministry of Health and Family Welfare websites also. This review describes the etiopathogenesis of nCovid19, including the mutation and origin of variants seen so far. We recapitulate existing knowledge of clinical features, investigations, and treatment strategies followed. The various complications seen in nCovid19 recovery patients are also elaborated with a focus on the alarming surge of mucormycosis and mortality in post-nCovid19-affected persons. © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

COVID-19: Origin, epidemiology, virology, pathogenesis, and treatment

COVID-19 (or Coronavirus Disease) originated in China (Hubei provenance, Wuhan city). The first recorded illness occurred in December 2019. It has affected all parts of the world, and the WHO designated the COVID-19 disease, caused by the new Coronavirus SARS-CoV-2, a pandemic on March 11, 2020. Some debatable speculations indicate that it is a man-made virus, intentionally synthesized in the laboratory but was unintentionally emancipated from a laboratory of Wuhan, China. The primitive theory suggested the spread from the Hunan seafood market of China probably from an animal source. However, this theory is not fully supported. COVID-19 infection has a varying range of signs and symptoms from low fever, dry cough to lower respiratory tract infection, breathing difficulties, pulmonary edema, acute respiratory distress syndrome (ARDS), metabolic acidosis, sepsis, coagulation, lymphopenia, hypoxemia, multiorgan failure, and eventually, mortality. In patients with comorbidity such as diabetes, cardiovascular disease, high blood pressure, stroke, and kidney disease, fatality rate is higher. Young and elderly people are more likely to experience unfavorable outcomes due to poor immunity. There have been several treatment methods explored to tackle the COVID-19 pandemic, including medications, interferon, vaccines, oligonucleotides, peptides, and monoclonal and immunomodulatory antibodies, among other things. The World Health Organization has recommended preventive measures like washing hands, using face masks, sanitizers, and maintaining a safe distance to prevent the spread of the pandemic. One of the promising alternatives is the vaccine. One must take all preventive measures in the pandemic until it becomes feeble. © 2022 Elsevier Inc. All rights reserved.

Thromboprophylaxis with standard-dose vs. flexible-dose heparin for hospitalized COVID-19 patients: a target trial emulation.

OBJECTIVES: To compare mortality of hospitalized COVID-19 patients under two low-molecular weight heparin (LMWH) thromboprophylaxis strategies: standard dose and variable dose (standard dose increased to intermediate dose in the presence of laboratory abnormalities indicating an increased thrombosis risk). STUDY DESIGN AND SETTING: Target trial emulation using observational data from 2,613 adults admitted with a COVID-19 diagnosis in Madrid, Spain between March 16 and April 15, 2020. RESULTS: A total of 1,284 patients were eligible. Among 503 patients without increased baseline thrombotic risk, 28-day mortality risk (95% confidence interval [CI]) was 9.0% (6.6, 11.7) under the standard dose strategy and 5.6% (3.3, 8.3) under the variable dose strategy; risk difference 3.4% (95% CI: -0.24, 6.9); mortality hazard ratio 1.61 (95% CI: 0.97, 2.89). Among 781 patients with increased baseline thrombotic risk, the 28-day mortality risk was 25.8% (22.7, 29.0) under the standard dose strategy and 18.1% (9.3, 28.9) under the intermediate dose strategy; risk difference 7.7% (95% CI: -3.5, 17.2); mortality hazard ratio 1.45 (95% CI: 0.81, 3.17). Major bleeding and LMWH-induced coagulopathy were rare under all strategies. CONCLUSION: Escalating anticoagulation intensity after signs of thrombosis risk may increase the survival of hospitalized COVID-19 patients. However, effect estimates were imprecise and additional studies are warranted.

Brazilian guidelines for the treatment of outpatients with suspected or confirmed COVID-19. A joint guideline of the Brazilian Association of Emergency Medicine (ABRAMEDE), Brazilian Medical Association (AMB), Brazilian Society of Angiology and Vascular Surgery (SBACV), Brazilian Society of Geriatrics and Gerontology (SBGG), Brazilian Society of Infectious Diseases (SBI), Brazilian Society of Family and Community Medicine (SBFMC), and Brazilian Thoracic Society (SBPT).

BACKGROUND: Several therapies have been used or proposed for the treatment of COVID-19, although their effectiveness and safety have not been properly evaluated. The purpose of this document is to provide recommendations to support decisions about the drug treatment of outpatients with COVID-19 in Brazil. METHODS: A panel consisting of experts from different clinical fields, representatives of the Brazilian Ministry of Health, and methodologists (37 members in total) was responsible for preparing these guidelines. A rapid guideline development method was used, based on the adoption and/or adaptation of recommendations from existing international guidelines combined with additional structured searches for primary studies and new recommendations whenever necessary (GRADE-ADOLOPMENT). The rating of quality of evidence and the drafting of recommendations followed the GRADE method. RESULTS: Ten technologies were evaluated, and 10 recommendations were prepared. Recommendations were made against the use of anticoagulants, azithromycin, budesonide, colchicine, corticosteroids, hydroxychloroquine/chloroquine alone or combined with azithromycin, ivermectin, nitazoxanide, and convalescent plasma. It was not possible to make a recommendation regarding the use of monoclonal antibodies in outpatients, as their benefit is uncertain and their cost is high, with limitations of availability and implementation. CONCLUSION: To date, few therapies have demonstrated effectiveness in the treatment of outpatients with COVID-19. Recommendations are restricted to what should not be used, in order to provide the best treatment according to the principles of evidence-based medicine and to promote resource savings by aboiding ineffective treatments.

Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units.

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients.

Racing to immunity: Journey to a COVID-19 vaccine and lessons for the future.

SARS-CoV-2 is the novel coronavirus behind the COVID-19 pandemic. Since its emergence, the global scientific community has mobilized to study this virus, and an overwhelming effort to identify COVID-19 treatments is currently ongoing for a variety of therapeutics and prophylactics. To better understand these efforts, we compiled a list of all COVID-19 vaccines undergoing preclinical and clinical testing using the WHO and ClinicalTrials.gov database, with details surrounding trial design and location. The most advanced vaccines are discussed in more detail, with a focus on their technology, advantages and disadvantages, as well as any available recent clinical findings. We also cover some of the primary challenges, safety concerns and public responses to COVID-19 vaccine trials, and consider what this can mean for the future. By compiling this information, we aim to facilitate a more thorough understanding of the extensive COVID-19 clinical testing vaccine landscape as it unfolds, and better highlight some of the complexities and challenges being faced by the joint effort of the scientific community in finding a prophylactic against COVID-19.

[Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units]. / Recomendaciones para el manejo de los pacientes críticos con COVID-19 en las Unidades de Cuidados Intensivos.

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients.

Anti-interleukin 6 receptor antibody treatment in patients with COVID-19, is it key to reduce mortality? / Tratamiento con el anticuerpo contra el receptor de la interleucina 6 en pacientes con COVID-19, ¿clave para reducir la mortalidad?

Interleukin 6 receptor antagonists are used for the treatment of severe chronic inflammatory diseases. Recently they have been proposed as a treatment for severe COVID-19 patients. However, there is scarce scientific evidence to support this, which is why it is necessary to generate scientific evidence and perform clinical trials to evaluate the appropriateness of this therapeutic strategy.

Los antagonistas del receptor de la interleucina 6 se usan para el tratamiento de diversas enfermedades inflamatorias crónicas. Recientemente se han propuesto para el tratamiento de los pacientes con COVID-19 grave. Sin embargo, hasta ahora la evidencia científica para respaldar esta intervención es escasa, por lo que es necesario generar mayor evidencia científica y hacer ensayos clínicos que permitan evaluar la pertinencia de esta estrategia terapéutica.

Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study.

CONTEXT: Calcifediol has been proposed as a potential treatment for COVID-19 patients. OBJECTIVE: To compare the administration or not of oral calcifediol on mortality risk of patients hospitalized because of COVID-19. DESIGN: Retrospective, multicenter, open, non-randomized cohort study. SETTINGS: Hospitalized care. PATIENTS: Patients with laboratory-confirmed COVID-19 between 5 February and 5 May 2020 in five hospitals in the South of Spain. INTERVENTION: Patients received calcifediol (25-hydroxyvitamin D3) treatment (0.266 mg/capsule, 2 capsules on entry and then one capsule on day 3, 7, 14, 21, and 28) or not. MAIN OUTCOME MEASURE: In-hospital mortality during the first 30 days after admission. RESULTS: A total of 537 patients were hospitalized with COVID-19 (317 males (59%), median age, 70 years), and 79 (14.7%) received calcifediol treatment. Overall, in-hospital mortality during the first 30 days was 17.5%. The OR of death for patients receiving calcifediol (mortality rate of 5%) was 0.22 (95% CI, 0.08 to 0.61) compared to patients not receiving such treatment (mortality rate of 20%; p < 0.01). Patients who received calcifediol after admission were more likely than those not receiving treatment to have comorbidity and a lower rate of CURB-65 score for pneumonia severity ≥ 3 (one point for each of confusion, urea > 7 mmol/L, respiratory rate ≥ 30/min, systolic blood pressure < 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age ≥ 65 years), acute respiratory distress syndrome (moderate or severe), c-reactive protein, chronic kidney disease, and blood urea nitrogen. In a multivariable logistic regression model, adjusting for confounders, there were significant differences in mortality for patients receiving calcifediol compared with patients not receiving it (OR = 0.16 (95% CI 0.03 to 0.80). CONCLUSION: Among patients hospitalized with COVID-19, treatment with calcifediol, compared with those not receiving calcifediol, was significantly associated with lower in-hospital mortality during the first 30 days. The observational design and sample size may limit the interpretation of these findings.

Clinical outcomes of patients hospitalized for COVID-19 and evidence-based on the pharmacological management reduce mortality in a region of the Colombian Caribbean.

INTRODUCTION: Despite the high volume of infections, some clinical aspects of this disease are still unknown. There are currently no studies in Colombia that describe the disease's clinical and treatment aspects in detail. OBJECTIVE: Describe the characteristics and clinical management of a group of admitted patients with SARS-CoV-2 infection in a private clinic in Montería, Córdoba-Colombia. PATIENTS AND METHODS: A descriptive observational study was carried out between May and August 2020 in 209 hospitalized patients with a confirmed diagnosis of COVID-19. Upon admittance, clinical, sociodemographic characteristics, comorbidities, and complications were analyzed. Additionally, the effect of the following medications was described: 1-antibiotics (cefepime, piperacillin, tazobactam, meropenem, vancomycin) + low molecular weight heparin (LMWH) + corticosteroids (dexamethasone-methylprednisolone) + colchicine. 2- Antibiotic + LMWH + corticosteroids. 3-LMWH + corticosteroids. 4-LMWH + corticosteroids + colchicine. 5-Other treatments (Tocilizumab). RESULTS: 107 (51%) of the 209 patients with a confirmed diagnosis of COVID-19 passed away. The main comorbidities related to mortality of these hospitalized patients with COVID-19 were obesity and kidney disease (P < 0.05). The main complications associated with fatal outcomes in this group of patients were Acute Respiratory Distress Syndrome (ARDS) and sepsis (P < 0.05). Furthermore, it was evidenced that the colchicine combination showed a significant difference in reducing mortality in hospitalized patients compared to the other therapeutic regimens (P < 0.05). CONCLUSION: A mortality rate of 51% was found attributable to several factors such as advanced age, obesity, kidney disease, and an average time in days of late consultation. The implementation of the colchicine combination could reduce the mortality rate in this disease.