COVID-19: How Effective Are the Repurposed Drugs and Novel Agents in Treating the Infection?

Coronavirus disease 2019 (COVID-19) induced by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has impacted the lives and wellbeing of many people. This globally widespread disease poses a significant public health concern that urges to discover an effective treatment. This review paper discusses the effectiveness of repurposed drugs used to treat COVID-19 and potential novel therapies for COVID-19. Among the various repurposed drugs, remdesivir is the only agent approved by the Food and Drug Administration (FDA) to treat COVID-19. On the other hand, several drugs have been listed in the Emergency Use Authorization (EUA) by the FDA to treat COVID-19, including casirivimab and imdevimab, baricitinib (in combination with remdesivir), bamlanivimab, tocilizumab, and IL-6 inhibitors. In addition, in vitro and clinical studies have suggested cepharanthine, sotrovimab, and XAV-19 as potential treatments to manage COVID-19. Due to inadequate understanding of COVID- 19 and the rapid mutation of SARS-CoV-2, COVID-19 remains a threat to global public health, with vaccination considered the most effective method to decrease COVID-19 transmission currently. Nevertheless, with the intense efforts of clinical researchers globally, more promising treatments for COVID-19 will be established in the future.

Angiotensin in shock

Angiotensin II is a potent vasoconstrictor agent, but until recently there has been little interest in using it as a therapeutic agent in hypotensive conditions. In an ovine model of sepsis with acute kidney injury, we demonstrated that angiotensin II restored arterial pressure and improved renal function, without adverse effects. Importantly, unlike noradrenaline, angiotensin II did not worsen sepsis-induced renal medullary hypoxia. Following these preclinical studies, angiotensin II was developed as a treatment (Giapreza®) for vasodilatory shock. The safety and efficacy of angiotensin II have been examined in numerous clinical trials that indicate it effectively restores arterial pressure in patients with sepsis, COVID-19, and postoperative vasoplegia. In the ATHOS-3 trial, in those patients who received renal replacement therapy, 28-day survival was greater with earlier liberation from renal replacement therapy. In those patients with increased plasma renin concentrations, mortality was reduced, and release from renal replacement therapy and ICU discharge occurred earlier. Thus, angiotensin II appears to be an effective treatment for vasodilatory shock, and further examination of its efficacy as a primary vasopressor and optimization of the choice of patient based on renin levels is warranted. © 2023 Elsevier Inc. All rights reserved.

ICU capacity expansion under uncertainty in the early stages of a pandemic

We propose a general modular approach to support decision-makers' response in the early stages of a pandemic with resource expansion, motivated by the shortage of Covid-19-related intensive care units (ICU) capacity in 2020 in Italy. Our approach uses (1) a stochastic extension of an epidemic model for scenarios of projected infections, (2) a capacity load model to translate infections into scenarios of demand for the resources of interest, and (3) an optimization model to allocate this demand to the projected levels of resources based on different values of investment. We demonstrate this approach with the onset of the first and second Covid-19 waves in three Italian regions, using the data available at that time. For epidemic modeling, we used a parsimonious stochastic susceptible-infected-removed model with a robust estimation procedure based on bootstrap resampling, suitable for a noisy and data-limited environment. For capacity loading, we used a Cox queuing model to translate the projected infections into demand for ICU, using stochastic intensity to capture the variability of the patient arrival process. Finally, we used stochastic dynamic optimization to select the best policy (when and how much to expand) to minimize the expected number of patients denied ICU for any level of investment in capacity expansion and obtain an efficient frontier. The frontier allows a trade-off between investment in additional resources and the number of patients denied intensive care. Moreover, in the panic-driven early days of a pandemic, decision-makers can also obtain the time until which they can postpone action, potentially reducing investment costs without increasing the expected number of denied patients. © 2023 The Authors. Production and Operations Management published by Wiley Periodicals LLC on behalf of Production and Operations Management Society.

Lessons from the pandemic: Responding to emerging zoonotic viral diseases-a Keystone Symposia report.

The COVID-19 pandemic caught the world largely unprepared, including scientific and policy communities. On April 10-13, 2022, researchers across academia, industry, government, and nonprofit organizations met at the Keystone symposium "Lessons from the Pandemic: Responding to Emerging Zoonotic Viral Diseases" to discuss the successes and challenges of the COVID-19 pandemic and what lessons can be applied moving forward. Speakers focused on experiences not only from the COVID-19 pandemic but also from outbreaks of other pathogens, including the Ebola virus, Lassa virus, and Nipah virus. A general consensus was that investments made during the COVID-19 pandemic in infrastructure, collaborations, laboratory and manufacturing capacity, diagnostics, clinical trial networks, and regulatory enhancements-notably, in low-to-middle income countries-must be maintained and strengthened to enable quick, concerted responses to future threats, especially to zoonotic pathogens.

Serology assays used in SARS-CoV-2 seroprevalence surveys worldwide: a systematic review and meta-analysis of assay features, testing algorithms, and performance (preprint)

Background: Many SARS-CoV-2 serological assays were rapidly developed during the COVID-19 pandemic. However, differences in detection mechanism limit the comparability of assay outputs. Methods: As part of the SeroTracker global living systematic review of SARS-CoV-2 seroprevalence studies, we collated serological assays used in serosurveys between January 1, 2020 and November 19, 2021. We mapped performance metrics to the manufacturer, third-party head-to-head, and independent group evaluations, comparing the assay performance data using a mixed-effect beta regression model. Results: Among 1807 serosurveys, 192 distinctive commercial assays and 380 self-developed assays were identified. According to manufacturers, 28.6% of all commercial assays met WHO criteria for emergency use (sensitivity [Sn.] >= 90.0%, specificity [Sp.] >= 97.0%). Third-party and independent evaluations indicated that manufacturers overstated the Sn. of their assays by 5.4% and 2.8%, and Sp. by 6.3% and 1.2%. We found in simulations that inaccurate Sn. and Sp. can substantially bias seroprevalence estimates corrected for assay performance. Conclusions: The Sn. and Sp. of the serological assay are not fixed properties, but varying features depending on testing population. To achieve precise population estimates and to ensure comparability, serosurveys should select assays with strong, independently validated performance and adjust seroprevalence estimates based on assured performance data.

Meeting nutritional requirements in critically-ill patients with COVID-19: Does the patient's position really matter?

Introduction: Prone positioning and veno-venous extracorporeal membrane oxygenation (VV-ECMO) can improve oxygenation in patients with COVID 19-induced acute respiratory distress syndrome (ARDS).1 Enteral feeding in the prone position has challenges, including possible aspiration risk of gastric contents and potential for disruption to enteral feeding.2 National guidelines2 were implemented locally;including a reduction in the maximum acceptable gastric residual volume (GRV) and the avoidance of bolus feeding while patients were in prone position. Objectives: • To explore the nutritional adequacy of patients in the prone position with COVID-19 on our critical care unit during the second surge (November 2020-April 2021) • To compare nutritional adequacy of days when patients were in prone versus supine position • To identify any factors that impacted on nutritional adequacy • To provide recommendations for improvement Methods: Patients with COVID-19 who required intubation, were placed in prone position at any time during their admission and had been assessed by the dietitian, were included. Total daily energy and protein intakes, from enteral (EN) and parenteral nutrition (PN), propofol and intravenous glucose were obtained from our computerised information system (Metavision) for each full day. If nutritional aims were not met then reasons for this were investigated. Nutritional adequacy was defined as ≥ 80% of energy and protein received per day.3 Results: Data for 34 patients was collected (see Table 1). A total of 1142 ICU days were included: 106 (9.3%) prone position days and 1036 (90.7%) supine position days. Patients received EN on 1098 days (96.1%) and PN on 44 days (3.9%). Only 4 of the 44 PN days occurred whilst a patient was in the prone position (0.4%). On prone position days, patients received an average 80% of their prescribed energy and 56% of their prescribed protein requirements, compared with 95% prescribed energy and 84% prescribed protein on supine position days. The average received across both prone and supine position days was 94% energy and 82% of protein. The 4 most frequent barriers to meeting protein requirements when in prone position were: • Reduction of NG feed rate when GRV's were higher than maximum acceptable volume • Use of a standard 4g protein/100ml 'Out of Hours' enteral feed • Fasting for procedures • Failure to give protein supplement boluses when patient returned to supine position Conclusion: Patient position affected nutritional intake, with energy and protein intake being lower on prone position days compared with supine position days. As only 9.3% of total ICU days were prone position days, average energy and protein received across all days still achieved nutritional adequacy. An increase in a patient's prone position days during ICU admission is likely to result in greater nutritional deficit, particularly for protein. Recommendations to improve nutritional adequacy on prone position days: • Consider use of post-pyloric feeding to increase feed tolerance • Use of a higher protein 'out of hours' enteral feed • Raised awareness of standard fasting times to ensure minimum disruption to feeding • Consider administration of protein supplement boluses in prone position when GRV's are within the accepted range .

What are patient preferences for virtual consultations for orthopaedic rehabilitation? Results from a discrete choice experiment (DCE) and qualitative interviews

Keywords: Patient preferences, Virtual consultations, Musculoskeletal Purpose: Videoconferencing (VC) has been cited as being able to reduce the number of face-to-face (F2F) outpatient appointments over the next 10 years. VC has been shown to be acceptable, however, face to face care is still seen as the ‘gold standard’. The COVID-19 pandemic has highlighted the potential for VC. The subject of this paper continues our previous research into patient preferences for VC in an orthopaedic rehabilitation setting. It is assumed that a patient will choose the option that they prefer (as iy provides the most utility). A Discrete Choice Experiment (DCE) was designed to investigate the factors influencing preference for VC among patients attending orthopaedic rehabilitation. Qualitative interviews were conducted with a small sample of participants to support theorisation into why the identified factors were important. The purpose of this research was to identify factors that influence patient preferences for video consultations in an orthopaedic rehabilitation setting. To explain why these factors influence preference. Methods: Previous research from the CONNECT Project informed DCE development. The design of the DCE took into account best practice guidance (ISPOR good practice for conjoint analysis) during its development. An efficient fractional factorial design with 16 choice scenarios was created that identified all main effects and partial two-way interactions. To reduce the impact of cognitive fatigue the design was blocked into two ‘blocks’ of eight scenarios each. Three pilots were undertaken to refine the questionnaire, to ensure comprehension. Quantitative analysis uses a binary logit regression models. A small number of participants strongly in favour of F2F and VC were sampled for qualitative interview using content analysis to provide additional insight into the results. Results: Two hundred and nineteen and 61 participants completed the ‘Block 1’ and ‘Block 2’ questionnaire, respectively. The study was terminated early due to COVID-19;as paired questionnaires from ‘Block 1’ and ‘Block 2’ were required for analysis, only 61 questionnaires (122 patients) were used. Duration of appointment, time of day, patient qualifications, access to equipment, difficulty with activities, multiple health issues, travel costs significant predictors to preference, were significant predictors of preference. A simplified conceptual model has been developed to explain how these factors interact to inform preference;these include contextual, structural and relationship factors. Eight participants who strongly preferred F2F and five participants who strongly preferred VC were interviewed. These interviews provided underlying rationale for choices. Conclusion(s): We have successfully designed and conducted a discrete choice experiment that investigated the trade-offs between pathway factors for patients attending orthopaedic rehabilitation appointments. A conceptual model was designed to focus attention towards the factors that influences preferences. Impact: An understanding of factors, such as those identified from this study, will enable clinicians to identify patients who prefer virtual consultations. The model developed from this study can inform the development of future technologies, trials and qualitative work to further explore the mechanisms that influence preference. Funding acknowledgements: Anthony Gilbert is funded by a Health Education England (HEE) and National Institute for Health Research (NIHR), Clinical Doctoral Research Fellowship for this research project (ICA-CDRF-2017-03-025).

COVID-19-related motivation to lose weight on a digital weight loss program

Background: Obesity is considered a risk factor for severe COVID-19 illness. Thus, individuals with obesity may be especially motivated to lose weight because of COVID-19. To our knowledge, this is the first study to assess COVID-related motivators to lose weight and whether they predict weight loss. Methods: In this prospective study, 530 new users of a digital commercial weight loss program completed a baseline survey in January 2021 assessing overall motivation to lose weight due to COVID (one item: 'how much of your interest in losing weight is because of COVID-19 or its impact, however minor, on your life?'), and three specific COVID motivators. These specific motivators were measured by the validated Fear of COVID-19 scale (F-C), one item assessing motivation to improve eating habits which got worse during COVID-19 (EH-C), and one item assessing motivation to prevent diseases that could increase COVID-19 risk (D-C). The main outcome was weight loss at 2 months, extracted from self-reported weight on the program. Results: Participants were 84% female, had a median age of 46, mean baseline BMI of 32.12 (SD = 6.96), and lost 3.13kg (3.49%) at 2 months (SD = 2.72kg). Overall COVID motivation was high;66% reported that their interest in losing weight was due to COVID. There was high F-C (M = 25.2 out of 35) and EH-C (M = 7.7 out of 10), and moderate D-C (M = 5.4 out of 10). Despite high COVID-related motivation, overall motivation, F-C, and EH-C did not predict weight loss at 2 months. D-C marginally significantly predicted weight loss at 2 months (B = -. 09, p = .06). Conclusions: Results suggest that even though individuals showed initial high motivation due to COVID, it did not manifest in actual weight loss, except in the most at-risk individuals who sought to prevent diseases that put them at greater risk. Individuals may need support to translate initial COVID-related motivation to actual weight loss. Next, we will examine relationships between COVID motivators, vaccination status, and weight loss at 4 months.

COVID-19 Serology Control Panel Using the Dried-Tube Specimen Method.

The dried-tube specimen (DTS) procedure was used to develop the COVID-19 serology control panel (CSCP). The DTS offers the benefit of shipping materials without a cold chain, allowing for greater access without deterioration of material integrity. Samples in the panel were sourced from COVID-19 convalescent persons from March to May 2020. The immunoglobulin subtypes (total Ig, IgM, and IgG) and their respective reactivity to severe acute respiratory syndrome coronavirus 2 nucleocapsid, spike, and receptor-binding domain antigens of the samples were delineated and compared with the WHO International Standard to elucidate the exact binding antibody units of each CSCP sample and ensure the CSCP provides adequate reactivity for different types of serological test platforms. We distribute the CSCP as a kit with five coded tubes to laboratories around the world to be used to compare test kits for external quality assurance, for harmonizing laboratory testing, and for use as training materials for laboratory workers.

Research into policy: lessons from the COVID-19 pandemic.

There has been an unprecedented global effort by researchers from many disciplines to obtain and synthesize knowledge to inform policy responses to SARS-CoV-2. While many major advances have been made in generating and applying knowledge on a pandemic caused by a novel pathogen, some things could have been done better, as revealed by the devastating loss of life and economic impact on livelihoods and communities. We reflect on the context in which the pandemic emerged, characterized by underinvestment in public health and growing distrust in institutions, followed by an overview of three broad areas: generation of new knowledge, synthesis of existing knowledge, both what was known prior to the pandemic and what emerged during it, and the challenges of translating knowledge into policy. We also consider areas that were largely overlooked in the research effort. Across all areas, we aim to draw out relevant lessons for future research and public health practice.

Regional differences in the impact of the COVID-19 pandemic on food sufficiency in California, April-July 2020: implications for food programmes and policies.

OBJECTIVE: To evaluate regional differences in factors associated with food insufficiency during the initial months of the COVID-19 pandemic among three major metropolitan regions in California, a state with historically low participation rates in the Supplementation Nutrition Assistance Program, the nation's largest food assistance programme. DESIGN: Analysis of cross-sectional data from phase 1 (23 April-21 July 2020) of the US Census Household Pulse Survey, a weekly national online survey. SETTING: California, and three Californian metropolitan statistical areas (MSA), including San Francisco-Oakland-Berkeley, Los Angeles-Long Beach-Anaheim and Riverside-San Bernardino-Ontario MSA. PARTICIPANTS: Adults aged 18 years and older living in households. RESULTS: Among the three metropolitan areas, food insufficiency rates were lowest in the San Francisco-Oakland-Berkeley MSA. Measures of disadvantage (e.g., having low-income, being unemployed, recent loss of employment income and pre-pandemic food insufficiency) were widely associated with household food insufficiency. However, disadvantaged households in the San Francisco Bay Area, the area with the lowest poverty and unemployment rates, were more likely to be food insufficient compared with those in the Los Angeles-Long Beach-Anaheim and Riverside-San Bernardino-Ontario MSA. CONCLUSIONS: Food insufficiency risk among disadvantaged households differed by region. To be effective, governmental response to food insufficiency must address the varied local circumstances that contribute to these disparities.

COVID-19 Serology Control Panel Using the Dried Tube Specimen Method (preprint)

We used the dried tube specimen (DTS) procedure to develop the COVID-19 Serology Control Panel ( CSCP). The CSCP contains five well-characterized SARS-CoV-2 pooled plasma samples made available for labs around the world to compare test kits, use for external quality assurance, harmonize laboratory testing, and train laboratory workers.

T cell response to SARS-CoV-2 infection in humans: A systematic review.

BACKGROUND: Understanding the T cell response to SARS-CoV-2 is critical to vaccine development, epidemiological surveillance and disease control strategies. This systematic review critically evaluates and synthesises the relevant peer-reviewed and pre-print literature published from 01/01/2020-26/06/2020. METHODS: For this systematic review, keyword-structured literature searches were carried out in MEDLINE, Embase and COVID-19 Primer. Papers were independently screened by two researchers, with arbitration of disagreements by a third researcher. Data were independently extracted into a pre-designed Excel template and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. RESULTS: 61 articles were included. 55 (90%) studies used observational designs, 50 (82%) involved hospitalised patients with higher acuity illness, and the majority had important limitations. Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear. CONCLUSION: A complex pattern of T cell response to SARS-CoV-2 infection has been demonstrated, but inferences regarding population level immunity are hampered by significant methodological limitations and heterogeneity between studies, as well as a striking lack of research in asymptomatic or pauci-symptomatic individuals. In contrast to antibody responses, population-level surveillance of the T cell response is unlikely to be feasible in the near term. Focused evaluation in specific sub-groups, including vaccine recipients, should be prioritised.

Antibody response to SARS-CoV-2 infection in humans: A systematic review.

BACKGROUND: Progress in characterising the humoral immune response to Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has been rapid but areas of uncertainty persist. Assessment of the full range of evidence generated to date to understand the characteristics of the antibody response, its dynamics over time, its determinants and the immunity it confers will have a range of clinical and policy implications for this novel pathogen. This review comprehensively evaluated evidence describing the antibody response to SARS-CoV-2 published from 01/01/2020-26/06/2020. METHODS: Systematic review. Keyword-structured searches were carried out in MEDLINE, Embase and COVID-19 Primer. Articles were independently screened on title, abstract and full text by two researchers, with arbitration of disagreements. Data were double-extracted into a pre-designed template, and studies critically appraised using a modified version of the Public Health Ontario Meta-tool for Quality Appraisal of Public Health Evidence (MetaQAT) tool, with resolution of disagreements by consensus. Findings were narratively synthesised. RESULTS: 150 papers were included. Most studies (113 or 75%) were observational in design, were based wholly or primarily on data from hospitalised patients (108, 72%) and had important methodological limitations. Few considered mild or asymptomatic infection. Antibody dynamics were well described in the acute phase, up to around three months from disease onset, but the picture regarding correlates of the antibody response was inconsistent. IgM was consistently detected before IgG in included studies, peaking at weeks two to five and declining over a further three to five weeks post-symptom onset depending on the patient group; IgG peaked around weeks three to seven post-symptom onset then plateaued, generally persisting for at least eight weeks. Neutralising antibodies were detectable within seven to 15 days following disease onset, with levels increasing until days 14-22 before levelling and then decreasing, but titres were lower in those with asymptomatic or clinically mild disease. Specific and potent neutralising antibodies have been isolated from convalescent plasma. Cross-reactivity but limited cross-neutralisation with other human coronaviridae was reported. Evidence for protective immunity in vivo was limited to small, short-term animal studies, showing promising initial results in the immediate recovery phase. CONCLUSIONS: Literature on antibody responses to SARS-CoV-2 is of variable quality with considerable heterogeneity of methods, study participants, outcomes measured and assays used. Although acute phase antibody dynamics are well described, longer-term patterns are much less well evidenced. Comprehensive assessment of the role of demographic characteristics and disease severity on antibody responses is needed. Initial findings of low neutralising antibody titres and possible waning of titres over time may have implications for sero-surveillance and disease control policy, although further evidence is needed. The detection of potent neutralising antibodies in convalescent plasma is important in the context of development of therapeutics and vaccines. Due to limitations with the existing evidence base, large, cross-national cohort studies using appropriate statistical analysis and standardised serological assays and clinical classifications should be prioritised.

Addressing Personal Protective Equipment (PPE) Decontamination: Methylene Blue and Light Inactivates SARS-CoV-2 on N95 Respirators and Masks with Maintenance of Integrity and Fit (preprint)

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has resulted in severe shortages of personal protective equipment (PPE) necessary to protect front-line healthcare personnel. These shortages underscore the urgent need for simple, efficient, and inexpensive methods to decontaminate SARS-CoV-2-exposed PPE enabling safe reuse of masks and respirators. Efficient decontamination must be available not only in low-resourced settings, but also in well-resourced settings affected by PPE shortages. Methylene blue (MB) photochemical treatment, hitherto with many clinical applications including those used to inactivate virus in plasma, presents a novel approach for widely applicable PPE decontamination. Dry heat (DH) treatment is another potential low-cost decontamination method. MethodsMB and light (MBL) and DH treatments were used to inactivate coronavirus on respirator and mask material. We tested three N95 filtering facepiece respirators (FFRs), two medical masks (MMs), and one cloth community mask (CM). FFR/MM/CM materials were inoculated with SARS-CoV-2 (a Betacoronavirus), murine hepatitis virus (MHV) (a Betacoronavirus), or porcine respiratory coronavirus (PRCV) (an Alphacoronavirus), and treated with 10 {micro}M MB followed by 50,000 lux of broad-spectrum light or 12,500 lux of red light for 30 minutes, or with 75{degrees}C DH for 60 minutes. In parallel, we tested respirator and mask integrity using several standard methods and compared to the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method. Intact FFRs/MMs/CM were subjected to five cycles of decontamination (5CD) to assess integrity using International Standardization Organization (ISO), American Society for Testing and Materials (ASTM) International, National Institute for Occupational Safety and Health (NIOSH), and Occupational Safety and Health Administration (OSHA) test methods. FindingsOverall, MBL robustly and consistently inactivated all three coronaviruses with at least a 4-log reduction. DH yielded similar results, with the exception of MHV, which was only reduced by 2-log after treatment. FFR/MM integrity was maintained for 5 cycles of MBL or DH treatment, whereas one FFR failed after 5 cycles of VHP+O3. Baseline performance for the CM was variable, but reduction of integrity was minimal. InterpretationMethylene blue with light and DH treatment decontaminated masks and respirators by inactivating three tested coronaviruses without compromising integrity through 5CD. MBL decontamination of masks is effective, low-cost and does not require specialized equipment, making it applicable in all-resource settings. These attractive features support the utilization and continued development of this novel PPE decontamination method.