Severe Covid-19

Remdesivir for COVID-19 in Europe: will it provide value for money?

BackgroundGrowing evidence supports the use of remdesivir and tocilizumab for the treatment of hospitalized patients with severe COVID-19. The purpose of this study was to evaluate the use of remdesivir and tocilizumab for the treatment of severe COVID-19 in a community hospital setting.MethodsWe used a de-identified dataset of hospitalized adults with severe COVID-19 according to the National Institutes of Health definition (SpO2 < 94% on room air, a PaO2/FiO2 < 300 mm Hg, respiratory frequency > 30/min, or lung infiltrates > 50%) admitted to our community hospital located in Evanston Illinois, between March 1, 2020, and March 1, 2021. We performed a Cox proportional hazards regression model to examine the relationship between the use of remdesivir and tocilizumab and inpatient mortality. To minimize confounders, we adjusted for age, qSOFA score, noninvasive positive-pressure ventilation, invasive mechanical ventilation, and steroids, forcing these variables into the model. We implemented a sensitivity analysis calculating the E-value (with the lower confidence limit) for the obtained point estimates to assess the potential effect of unmeasured confounding.Figure 1. Kaplan–Meier survival curves for in-hospital death among patients treated with and without steroidsThe hazard ratio was derived from a bivariable Cox regression model. The survival curves were compared with a log-rank test, where a two-sided P value of less than 0.05 was considered statistically significant.Figure 2. Kaplan–Meier survival curves for in-hospital death among patients treated with and without remdesivirThe hazard ratio was derived from a bivariable Cox regression model. The survival curves were compared with a log-rank test, where a two-sided P value of less than 0.05 was considered statistically significant.ResultsA total of 549 patients were included. The median age was 69 years (interquartile range, 59 – 80 years), 333 (59.6%) were male, 231 were White (41.3%), and 235 (42%) were admitted from long-term care facilities. 394 (70.5%) received steroids, 192 (34.3%) received remdesivir, and 49 (8.8%) received tocilizumab. By the cutoff date for data analysis, 389 (69.6%) patients survived, and 170 (30.4%) had died. The bivariable Cox regression models showed decreased hazard of in-hospital death associated with the administration of steroids (Figure 1), remdesivir (Figure 2), and tocilizumab (Figure 3). This association persisted in the multivariable Cox regression controlling for other predictors (Figure 4). The E value for the multivariable Cox regression point estimates and the lower confidence intervals are shown in Table 1.Figure 3. Kaplan–Meier survival curves for in-hospital death among patients treated with and without tocilizumabThe hazard ratio was derived from a bivariable Cox regression model. The survival curves were compared with a log-rank test, where a two-sided P value of less than 0.05 was considered statistically significant.Figure 4. Forest plot on effect estimates and confidence intervals for treatmentsThe hazard ratios were derived from a multivariable Cox regression model adjusting for age as a continuous variable, qSOFA score, noninvasive positive-pressure ventilation, and invasive mechanical ventilation.Table 1. Sensitivity analysis of unmeasured confounding using E-valuesCI, confidence interval. Point estimate from multivariable Cox regression model. The E value is defined as the minimum strength of association on the risk ratio scale that an unmeasured confounder would need to have with both the exposure and the outcome, conditional on the measured covariates, to explain away a specific exposure-outcome association fully: i.e., a confounder not included in the multivariable Cox regression model associated with remdesivir or tocilizumab use and in-hospital death in patients with severe COVID-19 by a hazard ratio of 1.64-fold or 1.54-fold each, respectively, could explain away the lower confidence limit, but weaker confounding could not.ConclusionFor patients with severe COVID-19 admitted to our community hospital, the use of steroids, remdesivir, and tocilizumab were significantly associated with a slower progression to in-hospital death while controlling for other predictors included in the models.DisclosuresAll Authors: No reported disclosures

The purpose of the study is to evaluate the clinical effectiveness of remdesivir in hospitalized patients with severe COVD-19 during complex treatment according to the National Protocol of the Ministry of Health of Ukraine. Materials and methods. We used to the data of a retrospective cohort study in adult patients (≥ 18 years old) with severe COVID-19, who were admitted to the infectious diseases department No. 2 of the Volyn Regional Clinical Hospital from December 2020 to May 2021. The statistical analysis included a group of patients who received Remdesivir (n = 98) and a control group of patients who did not receive Remdesivir (n = 190), which was modified. Results. It was found that 98 patients (n = 98) with severe COVID-19 who received Remdesivir at a course dose of 600 mg in 91.8% of cases (n = 90) recovered, the average age of those who recovered was 56.8 ± 2.56 years. On average, the beginning of the infusion of Remdesivir upon admission to the infectious diseases hospital occurred on the 9th day from the first day of the disease. In 8.2 % (n = 8), Remdesivir did not help patients with severe COVID-19 who died in intensive care, the average age of the deceased was 68.5 ± 5.83 years. During the study, it was found that the use of Remdesivir on average from the 9th day of illness at a course dose of 600 mg did not additionally affect the rate of restoration of saturation in patients with severe COVID-19 at the time of discharge from the hospital, and as an additive drug did not additionally affect on the reduction of CRP in the complex therapy with Dexamethasone of severe COVID-19, and also did not affect the use and/or reduction of the use of antibacterial drugs in patients with severe COVID-19. The use of Remdesivir did not significantly affect the decrease in the number of days of hospitalization, however, it significantly influenced the time of normalization of body temperature and, on average, this decrease was 1.7 ± 0.6 days in patients with severe COVID-19 compared with the control group without antiviral drug. It was found that Remdesivir in a course dose of 600 mg does not negatively affect creatinine levels and does not lead to renal dysfunction in patients with severe COVID-19. Despite the fact that 91.8 % of patients who received Remdesivir recovered, there was no statistically significant reduction in mortality (р &gt; 0,05) in the age group of patients aged 56 to 79 years with severe COVID-19 when using Redmesivir in the second week of illness (median onset of antiviral therapy is 9 days), therefore, Remdesivir must be administered prior to the onset of severe COVID-19 with a hyperinflammatory condition. Key words: coronavirus disease, severe COVID-19, remdesivir, retrospective cohort study.

Hepatic Disorders With the Use of Remdesivir for Coronavirus 2019

Steroids for sepsis and ARDS: this eternal controversy remains with COVID-19

Predicting Severe Outcomes in COVID-19

After the World Health Organisation declared Coronavirus Disease 2019 (COVID-19) a global pandemic on March 11, 2020, it became clear that health professionals worldwide were facing a severe and unprecedented challenge. On March 28, the FDA issued an emergency use authorisation order for use of chloroquine and hydroxychloroquine in COVID-19 patients, and on May 1, 2020, the agency gave the same authorisation for use of remdesivir. Even though different treatment strategies are undergoing evaluation, particularly for severe COVID-19 cases requiring intensive care, the consensus regarding best treatment approach has not yet been reached. Earlier this year, Zhe Xu and colleagues provided a detailed case report of a 50-year-old man with COVID-19 in the Lancet Respiratory Medicine journal.1 This case is particularly interesting since it provides a detailed day-to-day account of the hospitalisation, laboratory parameters and histological findings in a patient who neither belonged to a very high-risk age group, nor did he have any other co-morbidity.2 The patient's assessment revealed an overactivation of T cells manifested by an increase in the Th17 subset of CD4+ T cells leading to increased production of IL-17 and IL-22 cytokines which in turn caused the cytokine release storm (CRS) with a rapid and severe deterioration of the patient's condition.1 Pathologic postmortem lung analysis revealed a high number of Th17 lymphocytes in alveolar spaces. Besides the referenced case report, there is emerging body of evidence supporting the role of IL-17 in the pathogenesis of severe COVID-19 disease, including two recent publications reviewing the immune response in patients with COVID-19, that further emphasise the Th17-type cytokine storm in pathogenesis of the disease.3, 4 Wu and Yang highlighted the Th17 response in CRS of COVID-19 and proposed using fedratinib, a Janus kinase 2 (JAK2) inhibitor which blocks downstream cellular Th17 signalling pathway, in the treatment of CRS of COVID-19 patients.3 However, in our view, JAK inhibition of intracellular enzymes would also be associated with significant disadvantages entailing unintended and/or off-target effects leading to difficulty in predicting JAK2 inhibitors' biological effects.5 Since the increase in Th17 CD4+ T cells is also found in several inflammatory diseases, such as in severe plaque psoriasis,6 we hypothesise that the use of IL-17 blocking agents could be beneficial in the treatment of severe COVID-19 cases. The ligation of IL-17 to IL-17RA initiates activation of transcription factors NFκB, IκBζ, API and C-EBP, which potentiate IL-17–induced transcription of the most potent proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, G-CSF and GM-CSF), chemokines involved in attracting and further recruitment of immune infiltrates (IL-8, CXCL1, CXCL2, CXCL5, CCL2, CCL7 and CCL20), and matrix metalloproteinases involved in tissue damage (MMP1, MMP3, MMP9, MMP12 and MMP13).5, 7 IL-17 has been demonstrated in blood and affected tissues of patients with COVID-19, and IL-6 levels were significantly increased on Days 2 and 3 of the patient's hospitalisation1; thus, IL-17 inhibitors, which block IL-6 and IL-8 secretion from innate immune system, like neutrophils, mast cells, γδ T cells and innate lymphoid cells (ILC3), could prove as safe and effective therapy for severe COVID-19 (Figure 1). A recent study by Liu et al. also revealed an increased IL-6 level as well as increased levels of several other proinflammatory Th1, Th2 and Th17 cytokines (e.g., IL-2, 4, 6, 7, 10, 12 and 17) in patients with severe COVID-19.8 Blockade of IL-17 alone has been shown as clinically effective in many circumstances and diseases, despite the presence of myriad of proinflammatory cytokines; nevertheless, relevance of mediators crucial for the CRS response remains to be elucidated.9, 10 IL-17 specifically boosts proinflammatory, but not antiviral gene expression in human cells infected with respiratory viruses by stimulating non immune cells (fibroblasts and epithelial cells) to produce increased amounts of proinflammatory cytokines and chemokines in response to viral infections that attract other immune cell types (for example, neutrophils) which can lead to increased morbidity while simultaneously remaining inefficient in preventing the pathogen's spread.11 To date, there have been three IL-17 blocking agents available: secukinumab, ixekizumab and brodalumab.5 Secukinumab and ixekizumab are monoclonal IgG1 antibodies that bind specifically to IL-17A and that have been demonstrated to be very effective in the treatment of severe plaque psoriasis.12 Both drugs have a quick onset of action, high efficacy, tolerability and a well-established safety profile which does not include a decrease in the lymphocyte count.5 The substantial decrease in the total number of lymphocytes was found in patients with severe COVID-19, and this seems to facilitate viral replication.13 In contrast to TNF-α inhibitors, IL-17 blocking agents are not associated with a decrease in lymphocyte count.14 Brodalumab, a human monoclonal IgG2κ antibody against IL-17 receptor A (IL-17RA), was shown to be superior to placebo and ustekinumab for psoriasis treatment, due to complete blockade of key mediators of the T helper 17 pathway.5 Brodalumab as an IL-17 receptor blocker could potentially offer improved efficacy; however, patient suicides reported during the AMAGINE trial involving brodalumab raised some concerns regarding the safety of this agent, even though causal relationship was not unequivocally demonstrated.5 We believe that secukinumab, a fully human monoclonal antibody which exhibits significantly lower immunogenicity potential in patients with moderate-to-severe plaque psoriasis compared to ixekizumab (a humanised monoclonal antibody), would be best suitable for the treatment of severe COVID-19 patients.15, 16 IL-17 blocking agents can suppress the production of several Th17 signature cytokines (including the effects of IL-6 and TNF-α on other types of cells), thus theoretically offering significant therapeutic potential for Th17-associated CRS in COVID-19. Owing to their parenteral administration, these drugs could also be used concomitantly with other antiviral drugs as well as in patients on ventilator support. Preclinical studies demonstrated that the response to severe swine-origin influenza A virus H1N1 (S-OIV) in mice was boosted by introduction of IL-17 blocking agents, which led to reduction in cell and fluid infiltrates and an improvement in severity of acute lung injury.8 Crowe et al. found IL-17RA signalling crucial for acute lung injury in response to pulmonary influenza infection. This finding suggests that therapeutic modulation of IL-17 signalling might be beneficial in treating immunopathology associated with pulmonary viral infections.17 Li et al. demonstrated that pandemic H1N1 influenza virus caused acute lung injury in an IL-17-dependent manner in mice.18 They also reported that the response to pandemic H1N1 influenza virus in mice was improved by IL-17-blocking agents, which reduced disease duration, as well as cellular and fluid infiltrates. IL-17 blocking agents decreased pulmonary recruitment of inflammatory cells, cytokine production by T cells and the formation of lung oedema without preventing virus clearance in mice.18 These broad beneficial effects support further the idea that IL-17 blocking agents might be tested as potential treatment in severe COVID-19 patients. Tocilizumab, a recombinant human monoclonal IgG1 antibody that specifically binds to soluble and membrane-bound IL-6 receptors, has been shown to be effective in the treatment of severe COVID-19 by blocking IL-6 signalling and its proinflammatory response.19, 20 Until now, several clinical trials have been registered in order to assess safety and efficacy of tocilizumab in the treatment of severe COVID-19 pneumonia in adult patients.19, 20 Since IL-17 inhibitors and tocilizumab share the common Th17 signalling pathway, IL-17 blocking agents could also prove as safe and effective therapy for severe COVID-19. They might be even more effective than tocilizumab, since IL-17 precedes synthesis of potent proinflammatory cytokines IL-6 and TNF-α. Moreover, subcutaneous route of administration of IL-17 blocking agents could prove more convenient than intravenous administration of tocilizumab. In the treatment of severe plaque psoriasis, secukinumab is administered subcutaneously in the dose of 300 mg once weekly during the first month of treatment, followed by a dose of 300 mg every 4 weeks. Ixekizumab is also administered subcutaneously 160 mg every 2 weeks during the first 3 months, followed by a dose of 160 mg every 4 weeks. The recommended brodalumab dose in the treatment of severe plaque psoriasis is 210 mg once weekly during the first 2 weeks of treatment, followed by a dose of 210 mg every 2 weeks administered subcutaneously. It is worth noting that IL-17 blocking agents have not yet been evaluated in clinical trials for severe COVID-19 and patients would not receive the same dosage as patients with severe plaque psoriasis. Also, the timing of IL-17 blocking agent administration to severe COVID-19 patients would be crucial. It would perhaps be best to begin the treatment in the middle stage of CRS, when a significant increase in IL-6 levels is to be expected.1, 21 While we currently do not have a vaccine or highly effective antiviral treatments for COVID-19, repurposing certain immunomodulators, such as IL-17 blocking agents, might help to prevent CRS in severe COVID-19 cases, thereby further improving patients' outcomes. Finally, in our new, COVID-19 directed worldwide reality and with the constraints of limited experimental evidence regarding IL-17 blocking agents in mind, the importance of drug repurposing and effective dosing scheme investigation through conduct of well designed, randomised and double blind controlled clinical trials cannot be overstated enough. There are no competing interests to declare. All authors have made equal contributions to the article.

Leadership is the capacity to help transform a vision of the future into reality. Individuals who can and will exercise leadership are like a river's current--a part past where we now stand, a part yet to come. We have an ongoing need to remember and to look toward the next "generation." A key responsibility of those here now, is to mentor and to create structures for mentoring, in order to maximize the flow and effectiveness of tomorrow's leaders. When recruiting organizational leaders, the recruitment and interview process must seek individuals who in addition to technical competence, also have demonstrated leadership in their prior work and activities. To exercise effective leadership, we must work to know who we are, how we relate to others, and the environment around us. "Servant leadership" is a perspective held by many throughout the rural health community and offers a key set attributes of leadership useful to rural health. To implement the Institute of Medicine's recommendations in Through Collaboration: the Future of Rural Health, we must develop leaders skilled in collaboration, both internal to their organization and across organizations. The National Advisory Committee on Rural Health and Human Services had it right when they said to the Secretary and to the rest of us, "the best way to honor Jim is to consciously work to help develop the next generation of rural health leaders." There are, of course, a multitude of leadership institutes, programs, and courses throughout America; this is not a call for yet another separate entity. But it is a call to each of us in rural health to assure that we are deliberate in how we identify "emerging leaders from and for rural communities and provide them with the training and resources to play a lead role in ensuring access to quality healthcare in their states and communities." Let's get started.

Clinical questionWhat is the role of remdesivir in the treatment of severe covid-19? This guideline was triggered by the ACTT-1 trial published in the New England Journal of Medicine on...

IntroductionA possible benefit has been suggested for early treatment of severe coronavirus disease 2019 (COVID-19) with remdesivir. The efficacy of this drug is controversial and could significantly influence the efficiency in healthcare systems. The objective is the methodological interpretation of subgroup analyzes according to starting of remdesivir treatment with respect to symptom onset of COVID-19.MethodsA search in Pubmed® database was performed. Randomized clinical trials (RCTs) with subgroup analysis regarding early and late use of remdesivir were selected. All endpoints were assessed using two methodologies. First methodology considered statistical interaction, pre-specification, biological plausibility, and consistency of results. Second methodology was a validated tool with preliminary questions to discard subset analysis without relevant minimum conditions, and a checklist with recommendations for applicability.ResultsA total of 54 results were found and five RCTs were selected. According first methodology, consistent heterogeneity was only found in time to clinical improvement and better clinical status score at day 15 for patients with severe COVID-19 and <7 days of symptoms. About second methodology, these results about early use of remdesivir may be applied to clinical practice with caution.ConclusionsWe developed a systematic search and application of an established methodology for interpretation of subgroup analysis about early use of remdesivir. Results in severe COVID-19 suggested that early use of remdesivir provides a greater benefit in <7 days of symptoms for time to clinical improvement and better clinical status score at day 15. Future studies could use 7-day cut-off of symptoms to evaluate remdesivir.

A look-back at convalescent plasma to treat COVID-19

Evolution of the Evidence for the Management of COVID-19 in Hematologic Malignancies: A Systematic Literature Review of Remdesivir

Introduction: Coronavirus disease 2019 (COVID-19) still has a high mortality rate when it is severe. Regdanvimab (CT-P59), a neutralizing monoclonal antibody that has been proven effective against mild to moderate COVID-19, may be effective against severe COVID-19. This study was conducted to determine the effectiveness of the combined use of remdesivir and regdanvimab in patients with severe COVID-19. Methods: From March to early May 2021, 124 patients with severe COVID-19 were admitted to Ulsan University Hospital (Ulsan, Korea) and received oxygen therapy and remdesivir. Among them, 25 were also administered regdanvimab before remdesivir. We retrospectively compared the clinical outcomes between the remdesivir alone group [n = 99 (79.8%)] and the regdanvimab/remdesivir group [n = 25 (20.2%)]. Results: The oxygen-free days on day 28 (primary outcome) were significantly higher in the regdanvimab/remdesivir group [mean ± SD: 19.36 ± 7.87 vs. 22.72 ± 3.66, p = 0.003]. The oxygen-free days was also independently associated with use of regdanvimab in the multivariate analysis, after adjusting for initial pulse oximetric saturation (SpO2)/fraction of inspired oxygen (FiO2) ratio (severity index). Further, in the regdanvimab/remdesivir group, the lowest SpO2/FiO2 ratio during treatment was significantly higher (mean ± SD: 237.05 ± 89.68 vs. 295.63 ± 72.74, p = 0.003), and the Kaplan-Meier estimates of oxygen supplementation days in surviving patients (on day 28) were significantly shorter [mean ± SD: 8.24 ± 7.43 vs. 5.28 ± 3.66, p = 0.024]. Conclusions: In patients with severe COVID-19, clinical outcomes can be improved by administering regdanvimab, in addition to remdesivir.

One year on: The impact of COVID-19 on clinical research

Cytokine storm is the most prominent hallmark in patients with coronavirus disease 2019 (COVID-19) that stimulates the free radical storm, both of which induce an overactive immune response during viral infection. We hypothesized that owning to its radical-scavenging and anti-inflammatory properties, Edaravone could reduce multi-organ injury, clinical complications, and mortality in severe COVID-19 cases. This single-center randomized clinical trial was accompanied in the intensive care units (ICUs) of the teaching hospital of Tabriz University of Medical Sciences to evaluate the effect of Edaravone on the outcome of patients with severe COVID-19. Thirty-eight patients admitted to ICU were included and randomized into two control and intervention arms. Patients in the intervention group received 30 mg Edaravone by slow intravenous infusion for three days in addition to receiving national therapy. The primary outcome was the need for intubation, the intubation length, and mortality rate. Secondary endpoints were clinical improvement. Edaravone administration improved the primary outcomes; it decreased the need for endotracheal intubation and mechanical ventilation [10.52% (n = 2) versus 42.1% (n = 8); p = 0.03] and intubation length [3 (1–7) versus 28 (4–28), p = 0.04] compared to control group. Baseline characteristics and laboratory tests were similar between the studied groups. No marked differences were observed in secondary endpoints (p > 0.05). Administration of Edaravone could decrease the need for mechanical ventilation and length of intubation in severe COVID-19 patients admitted to ICU.