Immunomodulators for immunocompromised patients hospitalized for COVID-19: a meta-analysis of randomized controlled trials.

Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61-1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64-1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09-0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

A combination of mild-moderate hypoxemia and low compliance is highly prevalent in persistent ARDS: a retrospective study.

BACKGROUND: The Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and edema, impairing both oxygenation and lung compliance. Recent studies reported a dissociation between oxygenation and compliance (severe hypoxemia with preserved compliance) in early ARDS and COVID-19-related-ARDS (CARDS). During the pandemic, in patients requiring prolonged mechanical ventilation, we observed the opposite combination (mild-moderate hypoxemia but significantly impaired compliance). The purpose of our study was to investigate the prevalence of this combination of mild-moderate hypoxemia and impaired compliance in persistent ARDS and CARDS. METHODS: For this retrospective study, we used individual patient-level data from two independent cohorts of ARDS patients. The ARDSNet cohort included patients from four ARDS Network randomized controlled trials. The CARDS cohort included patients with ARDS due to COVID-19 hospitalized in two intensive care units in Greece. We used a threshold of 150 for PaO2/FiO2 and 30 ml/cmH2O for compliance, estimated the prevalence of each of the four combinations of oxygenation and compliance at baseline, and examined the change in its prevalence from baseline to day 21 in the ARDSNet and CARDS cohorts. RESULTS: The ARDSNet cohort included 2909 patients and the CARDS cohort included 349 patients. The prevalence of the combination of mild-moderate hypoxemia and low compliance increased from baseline to day 21 both in the ARDSNet cohort (from 22.2 to 42.7%) and in the CARDS cohort (from 3.1 to 33.3%). Among surviving patients with low compliance, oxygenation improved over time. The 60-day mortality rate was higher for patients who had mild-moderate hypoxemia and low compliance on day 21 (28% and 56% in ARDSNet and CARDS), compared to those who had mild-moderate hypoxemia and high compliance (20% and 50%, respectively). CONCLUSIONS: Among patients with ARDS who require prolonged controlled mechanical ventilation, regardless of ARDS etiology, a dissociation between oxygenation and compliance characterized by mild-moderate hypoxemia but low compliance becomes increasingly prevalent. The findings of this study highlight the importance of monitoring mechanics in patients with persistent ARDS.

PROLONGED MECHANICAL VENTILATION IN ACUTE RESPIRATORY DISTRESS SYNDROME.

ABSTRACT: Purpose: Trajectory of acute respiratory distress syndrome (ARDS) spans from rapidly improving cases to cases receiving prolonged mechanical ventilation (PMV). We attempted to estimate temporal trends of prevalence and mortality of PMV and to identify risk factors associated with mortality of patients with ARDS receiving PMV. Methods: We performed a secondary analysis of individual patient data from six randomized controlled clinical trials conducted by the ARDS Network. Prolonged mechanical ventilation was defined as the need for mechanical ventilation for >21 consecutive days. Results: Of 4,216 patients with ARDS, 646 (15.3%) received PMV. Prevalence of PMV gradually declined from 18.4% in the ARDS Network: Low-Tidal-Volume Trial (published in 2000) trial to 10.9% in the SAILS (2014) trial ( R2 = 0.728, P = 0.031). Ninety-day mortality of patients receiving PMV did not change over time ( R2 = 0.271, P = 0.290) and remained as high as 36.8%. Ιn the three most recent trials, risk factors associated with mortality among the 250 patients with ARDS receiving PMV included age, malignancy, pneumonia as the cause of ARDS, coagulation dysfunction, and hepatic dysfunction during the first 21 days after trial enrollment. Conclusion: Although prevalence of PMV among patients enrolled in ARDS Network trials gradually declined, mortality did not change. Risk factors associated with mortality were mostly nonmodifiable.

Racial and ethnic minority participants in clinical trials of acute respiratory distress syndrome.

PURPOSE: There is growing interest in improving the inclusiveness of racial and ethnic minority participants in trials of acute respiratory distress syndrome (ARDS). With our study we aimed to examine temporal trends of representation and mortality of racial and ethnic minority participants in randomized controlled trials of ARDS. METHODS: We performed a secondary analysis of eight ARDS Network and PETAL Network therapeutic clinical trials, published between 2000 and 2019. We classified race/ethnicity into "White", "Black", "Hispanic", or "Other" (including Asian, American Indian or Alaskan Native, Native Hawaiian, or other Pacific Islander participants). RESULTS: Of 5375 participants with ARDS, 1634 (30.4%) were Black, Hispanic, or Other race participants. Representation of racial and ethnic minority participants in trials did not change significantly over time (p = 0.257). However, among participants with moderate to severe ARDS (i.e., partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 150), the difference in mortality between racial and ethnic minority participants and White participants decreased over time. In the five most recent trials, including 2923 participants with ARDS, there were no statistically significant differences in mortality between racial/ethnic groups, even after adjusting for potential confounders. In these five most recent trials, mortality was 31% for White, 31.9% for Black, 30.3% for Hispanic, and 37.1% for Other race participants (p = 0.633). CONCLUSION: Representation of racial and ethnic minority participants in ARDS trials from North America, published between 2000 and 2019, did not change over time. Black and Hispanic participants with ARDS may have similar mortality as White participants within trials.

Postoperative acute respiratory distress syndrome in randomized controlled trials.

BACKGROUND: Acute respiratory distress syndrome is a potentially fatal postoperative complication. We aimed to estimate temporal trends of the representation of patients with postoperative acute respiratory distress syndrome in clinical trials, determine their distinct clinical features, and identify predictors of mortality. METHODS: This is a secondary analysis of 7 randomized controlled clinical trials conducted by the Acute Respiratory Distress Syndrome Network and the Clinical Trials Network for the Prevention and Early Treatment of Acute Lung Injury. Patients with acute respiratory distress syndrome were classified into a postoperative acute respiratory distress syndrome group (ie, patients who had undergone elective surgery in the immediate period before trial enrollment) and a non-postoperative acute respiratory distress syndrome group. RESULTS: Out of 5,316 patients with acute respiratory distress syndrome, 256 (4.8%) had postoperative acute respiratory distress syndrome. Representation of postoperative acute respiratory distress syndrome in trials gradually declined from 2000 to 2011, but it remained stable afterward at 2.7%. Postoperative acute respiratory distress syndrome was associated with lower 90-day mortality (24.6% vs 30.9%, P = .032) than non-postoperative acute respiratory distress syndrome, even after adjusting for age, acute respiratory distress syndrome severity, usage of vasopressors at baseline, and the study publication year (hazard ratio 0.63, 95% confidence interval 0.49-0.82). Age (odds ratio 1.07, 95% confidence interval 1.04-1.09), immunosuppression (odds ratio 4.12, 95% confidence interval 1.43-11.86), and positive fluid balance (odds ratio 1.09, 95% confidence interval 1.04-1.14) were associated with 90-day mortality among patients with postoperative acute respiratory distress syndrome. CONCLUSION: Representation of postoperative acute respiratory distress syndrome in trials of the Acute Respiratory Distress Syndrome Network and the Clinical Trials Network for the Prevention and Early Treatment of Acute Lung Injury gradually declined from 2000 to 2011 but remained stable afterward. Postoperative acute respiratory distress syndrome was associated with lower mortality than non-postoperative acute respiratory distress syndrome. These findings may put both temporal trends and the prognosis of postoperative acute respiratory distress syndrome in perspective. Also, positive fluid balance was associated with the mortality of patients with postoperative acute respiratory distress syndrome.

Rapidly improving acute respiratory distress syndrome in COVID-19: a multi-centre observational study.

BACKGROUND: Before the pandemic of coronavirus disease (COVID-19), rapidly improving acute respiratory distress syndrome (ARDS), mostly defined by early extubation, had been recognized as an increasingly prevalent subphenotype (making up 15-24% of all ARDS cases), associated with good prognosis (10% mortality in ARDSNet trials). We attempted to determine the prevalence and prognosis of rapidly improving ARDS and of persistent severe ARDS related to COVID-19. METHODS: We included consecutive patients with COVID-19 receiving invasive mechanical ventilation in three intensive care units (ICU) during the second pandemic wave in Greece. We defined rapidly improving ARDS as extubation or a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) greater than 300 on the first day following intubation. We defined persistent severe ARDS as PaO2:FiO2 of equal to or less than 100 on the second day following intubation. RESULTS: A total of 280 intubated patients met criteria of ARDS with a median PaO2:FiO2 of 125.0 (interquartile range 93.0-161.0) on day of intubation, and overall ICU-mortality of 52.5% (ranging from 24.3 to 66.9% across the three participating sites). Prevalence of rapidly improving ARDS was 3.9% (11 of 280 patients); no extubation occurred on the first day following intubation. ICU-mortality of patients with rapidly improving ARDS was 54.5%. This low prevalence and high mortality rate of rapidly improving ARDS were consistent across participating sites. Prevalence of persistent severe ARDS was 12.1% and corresponding mortality was 82.4%. CONCLUSIONS: Rapidly improving ARDS was not prevalent and was not associated with good prognosis among patients with COVID-19. This is starkly different from what has been previously reported for patients with ARDS not related to COVID-19. Our results on both rapidly improving ARDS and persistent severe ARDS may contribute to our understanding of trajectory of ARDS and its association with prognosis in patients with COVID-19.

Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective.

Cell senescence constitutes a physiological process that serves as protection from malignant transformation of cells. However, recent scientific discoveries also identify cell senescence as pivotal in hepatocellular cancer (HCC) biology. The review herein aimed to accumulate evidence on senescence as a mediator of HCC occurrence in hepatitis B (HBV), C (HCV) virus infections, and non-alcoholic fatty liver disease (NAFLD). In HBV infection, the carcinogenic HBV X protein frequently mutates during chronic infection, and subsequently exhibits different effects on senescence. In HCV infection, senescent non-functional T-cells do not effectively clear pre-malignant hepatocytes. Furthermore, the HCV Core protein inhibits the occurrence of normal stress-induced hepatocyte senescence, allowing damaged cells to maintain their proliferative potential. In NAFLD-mediated HCC, current data point towards the gut microbiome and hepatic stellate cell senescence. Additionally, senescence contributes in the development of resistance in targeted therapies, such as sorafenib. Finally, the promising role of senotherapeutics in HCC was also explored. Overall, although we may still be at a primitive stage in fully unraveling the role of senescence in cancer, it seems that understanding and harnessing senescence may have the potential to revolutionize the way we treat hepatocellular cancer.

Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19.

Current standard treatment of COVID-19 lacks in effective antiviral options. Plitidepsin, a cyclic depsipeptide authorized in Australia for patients with refractory multiple myeloma, has recently emerged as a candidate anti-SARS-CoV-2 agent. The aim of this review was to summarize current knowledge on plitidepsin's clinical profile, anti-tumour and anti-SARS-CoV-2 mechanisms and correlate this with available or anticipated, preclinical or clinical evidence on the drug's potential for COVID-19 treatment.PubMed, Scopus, CENTRAL, clinicaltrials.gov, medRxiv and bioRxiv databases were searched.Plitidepsinexerts its anti-tumour and antiviral properties primarily through acting on isoforms of the host cell's eukaryotic-translation-elongation-factor-1-alpha (eEF1A). Through inhibiting eEF1A and therefore translation of necessary viral proteins, it behaves as a "host-directed" anti-SARS-CoV-2 agent. In respect to its potent anti-SARS-CoV-2 properties, the drug has demonstrated superior ex vivo efficacy compared to other host-directed agents and remdesivir, and it might retain its antiviral effect against the more transmittable B.1.1.7 variant. Its well-studied safety profile, also in combination with dexamethasone, may accelerate its repurposing chances for COVID-19 treatment. Preliminary findings in hospitalized COVID-19 patients, have suggested potential safety and efficacy of plitidepsin, in terms of viral load reduction and clinical resolution. However, the still incomplete understanding of its exact integration into host cell-SARS-CoV-2 interactions, its intravenous administration exclusively purposing it for hospital settings the and precocity of clinical data are currently considered its chief deficits. A phase III trial is being planned to compare the plitidepsin-dexamethasone regimen to the current standard of care only in moderately affected hospitalized patients. Despite plitidepsin's preclinical efficacy, current clinical evidence is inadequate for its registration in COVID-19 patients.Therefore, multicentre trials on the drug's efficacy, potentially also studying populations of emerging SARS-CoV-2 lineages, are warranted.

Effect of timing of intubation on clinical outcomes of critically ill patients with COVID-19: a systematic review and meta-analysis of non-randomized cohort studies.

BACKGROUND: Although several international guidelines recommend early over late intubation of patients with severe coronavirus disease 2019 (COVID-19), this issue is still controversial. We aimed to investigate the effect (if any) of timing of intubation on clinical outcomes of critically ill patients with COVID-19 by carrying out a systematic review and meta-analysis. METHODS: PubMed and Scopus were systematically searched, while references and preprint servers were explored, for relevant articles up to December 26, 2020, to identify studies which reported on mortality and/or morbidity of patients with COVID-19 undergoing early versus late intubation. "Early" was defined as intubation within 24 h from intensive care unit (ICU) admission, while "late" as intubation at any time after 24 h of ICU admission. All-cause mortality and duration of mechanical ventilation (MV) were the primary outcomes of the meta-analysis. Pooled risk ratio (RR), pooled mean difference (MD) and 95% confidence intervals (CI) were calculated using a random effects model. The meta-analysis was registered with PROSPERO (CRD42020222147). RESULTS: A total of 12 studies, involving 8944 critically ill patients with COVID-19, were included. There was no statistically detectable difference on all-cause mortality between patients undergoing early versus late intubation (3981 deaths; 45.4% versus 39.1%; RR 1.07, 95% CI 0.99-1.15, p = 0.08). This was also the case for duration of MV (1892 patients; MD - 0.58 days, 95% CI - 3.06 to 1.89 days, p = 0.65). In a sensitivity analysis using an alternate definition of early/late intubation, intubation without versus with a prior trial of high-flow nasal cannula or noninvasive mechanical ventilation was still not associated with a statistically detectable difference on all-cause mortality (1128 deaths; 48.9% versus 42.5%; RR 1.11, 95% CI 0.99-1.25, p = 0.08). CONCLUSIONS: The synthesized evidence suggests that timing of intubation may have no effect on mortality and morbidity of critically ill patients with COVID-19. These results might justify a wait-and-see approach, which may lead to fewer intubations. Relevant guidelines may therefore need to be updated.

Galectins-1, -3, -7, -8 and -9 as prognostic markers for survival in epithelial ovarian cancer: A systematic review and meta-analysis.

BACKGROUND: Galectins are a family of proteins that have recently emerged as regulators of cancer biology. OBJECTIVES: To investigate the impact of peritumoral and tumoral galectin expression on ovarian cancer prognosis. SEARCH STRATEGY: We searched Medline, Cochrane, and EMBASE databases from inception until March 22, 2020. SELECTION CRITERIA: All studies correlating galectins and ovarian cancer prognosis were selected. DATA COLLECTION AND ANALYSIS: The literature search presented 11 studies, which contained 1034 patients. Meta-analysis was performed with RevMan 5.3 software. MAIN RESULTS: Studies were stratified into two groups depending on the location of galectin expression (peritumoral stroma or nucleus/cytoplasm of tumor cells). Tumoral galectin-7 and galectin-9 expression was significantly associated with poor overall survival (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.32-3.21, P = 0.001; OR 1.71, 95% CI 1.27-2.30, P < 0.001, respectively). The total effect of high tumoral expression of galectins in overall survival and progression-free survival was significant (OR 1.51, 95% CI 1.02-2.23, P = 0.04; OR 2.76, 95% CI 1.73-4.40, P < 0.001, respectively). CONCLUSIONS: Our results suggest that galectins are implicated in ovarian cancer prognosis; however, further research is needed to ascertain their actual importance as well as their diagnostic accuracy.

Clinicopathological Data and Treatment Modalities for Pancreatic Somatostatinomas.

BACKGROUND/AIM: Somatostatinomas (SSomas) constitute a rare neuroendocrine tumor. The purpose of this study was to evaluate the current published literature about pancreatic SSomas and report epidemiologic and clinicopathologic data for this entity. PATIENTS AND METHODS: A combined automated and manual systematic database search of the literature was performed using electronic search engines (Medline PubMed, Scopus, Ovid and Cochrane Library), until February 2020. Statistical analysis was performed using the R language and environment for statistical computing. RESULTS: Overall, the research revealed a total of 36 pancreatic SSoma cases. Patient mean age was 50.25 years. The most common pancreatic location was the pancreatic head (61.8%). The most frequent clinical symptom was abdominal pain (61.1%). Diagnostic algorithm most often included Computed Tomography and biopsy; surgical resection was performed in 28 cases. Out of the 36 cases, 22 had been diagnosed with a metastatic tumor and metastasectomy was performed in 6 patients with a worse overall survival (OS) (p=0.029). In total, OS was 47.74 months. CONCLUSION: Patients with metastatic disease did not benefit from metastasectomy, but the sample size was small to reach definite conclusions. However, further studies with longer follow-up are needed for a better evaluation of these results.

Global burden of COVID-19 pandemic on healthcare workers.

Provision of PPE, placing experienced HCWs mostly in organisational positions, increasing testing, minimising exposure by adjusting shift schedules, and providing food and sleep facilities could be some restorative measures to protect HCWs from #COVID19 https://bit.ly/2zcVARW.

Effect of Cancer on Clinical Outcomes of Patients With COVID-19: A Meta-Analysis of Patient Data.

PURPOSE: Whether cancer is associated with worse prognosis among patients with COVID-19 is unknown. We aimed to quantify the effect (if any) of the presence as opposed to absence of cancer on important clinical outcomes of patients with COVID-19 by carrying out a systematic review and meta-analysis. METHODS: We systematically searched PubMed, medRxiv, COVID-19 Open Research Dataset (CORD-19), and references of relevant articles up to April 27, 2020, to identify observational studies comparing patients with versus without cancer infected with COVID-19 and to report on mortality and/or need for admission to the intensive care unit (ICU). We calculated pooled risk ratios (RR) and 95% CIs with a random-effects model. The meta-analysis was registered with PROSPERO (CRD42020181531). RESULTS: A total of 32 studies involving 46,499 patients (1,776 patients with cancer) with COVID-19 from Asia, Europe, and the United States were included. All-cause mortality was higher in patients with versus those without cancer (2,034 deaths; RR, 1.66; 95% CI, 1.33 to 2.07; P < .0001; 8 studies with 37,807 patients). The need for ICU admission was also more likely in patients with versus without cancer (3,220 events; RR, 1.56; 95% CI, 1.31 to 1.87; P < .0001; 26 studies with 15,375 patients). However, in a prespecified subgroup analysis of patients > 65 years of age, all-cause mortality was comparable between those with versus without cancer (915 deaths; RR, 1.06; 95% CI, 0.79 to 1.41; P = .71; 8 studies with 5,438 patients). CONCLUSION: The synthesized evidence suggests that cancer is associated with worse clinical outcomes among patients with COVID-19. However, elderly patients with cancer may not be at increased risk of death when infected with COVID-19. These findings may inform discussions of clinicians with patients about prognosis and may guide health policies.

Prevalence of depression, anxiety, and insomnia among healthcare workers during the COVID-19 pandemic: A systematic review and meta-analysis.

BACKGROUND: COVID-19 pandemic has the potential to significantly affect the mental health of healthcare workers (HCWs), who stand in the frontline of this crisis. It is, therefore, an immediate priority to monitor rates of mood, sleep and other mental health issues in order to understand mediating factors and inform tailored interventions. The aim of this review is to synthesize and analyze existing evidence on the prevalence of depression, anxiety and insomnia among HCWs during the Covid-19 outbreak. METHODS: A systematic search of literature databases was conducted up to April 17th, 2020. Two reviewers independently assessed full-text articles according to predefined criteria. Risk of bias for each individual study was assessed and data pooled using random-effects meta-analyses to estimate the prevalence of specific mental health problems. The review protocol is registered in PROSPERO and is available online. FINDINGS: Thirteen studies were included in the analysis with a combined total of 33,062 participants. Anxiety was assessed in 12 studies, with a pooled prevalence of 23·2% and depression in 10 studies, with a prevalence rate of 22·8%. A subgroup analysis revealed gender and occupational differences with female HCPs and nurses exhibiting higher rates of affective symptoms compared to male and medical staff respectively. Finally, insomnia prevalence was estimated at 38·9% across 5 studies. INTERPRETATION: Early evidence suggests that a considerable proportion of HCWs experience mood and sleep disturbances during this outbreak, stressing the need to establish ways to mitigate mental health risks and adjust interventions under pandemic conditions.